Azetidinimines as Carbapenemases Inhibitors

ABSTRACT

The present application relates to novel azetidinimine of formula (I). Wherein R 1 -R 6  are as defined in claim  1 . The azetidinimine of the invention are useful as antibiotics and as inhibitors of a carbapenemases. The present invention thus further relates to their use in antibiotic therapies and their methods of synthesis.

The subject matter of the present application concerns novel products(azetidinimine) for their use in antibiotic therapies and their methodsof synthesis.

INTRODUCTION

Antibiotics are commonly used in order to kill and/or block the growthof micro-organisms responsible of pathologies.

Although there are several families of antibiotics with differentstructures, the way these antibiotics act, however remains similar onesin comparison with each others. Among these antibiotics, there areβ-lactams characterized by a β-lactam nucleus responsible for theirbiological activity. Most famous β-lactams are mostly derived frompenicillins, cephalosporins, and carbapenems monobactams. However, onemajor problem is the resistance that bacteria develop to counter theaction of these antibiotics by enzymes called β-lactamase which cuts theC(O)—N bond in the following manner:

To counter this phenomenon, it is useful to develop inhibitors ofβ-lactamases, more specifically carbapenemases inhibitors.

In this perspective, the antibiotic resistances of bacteria, inparticular K. pneumoniae, E. coli and E. cloacae, are of great concerntoday. Studies have shown that the essential cause of these particularresistances are due to several types of enzymes and more specificallycarbapenemases metallo-enzyme NDM-1 (12%), type oxacillinases OXA-48(67%) and class A KPC-2 (14%).

Monobactam fonctions have been targeted in the art directly to induceantibiotic activities or have been used as β-lactamase inhibitors.

Examples of such antibiotics are e.g.:

Examples of such inhibitors are e.g.:

The antibiotic activity of the β-lactam feature is essentially due tothe instability of the amide bond which can be cleaved in the presenceof enzymes according to the following mechanism:

The amide bond is weakened by the delocalization of the non-bindingelectrons of the nitrogen adjacent to the carbonyl. Thus, in order togenerate inhibitory molecules of β-lactamases, as “suicide molecules”capable of opening themselves faster than the antibiotic substance, ithas been envisaged in the context of the present invention thepreparation of structures in which the carbonyl group is replaced withunsaturated electrophilic groups. Indeed, few studies in this area havebeen reported in the literature.

In this context, it has been chosen to direct efforts towards thesynthesis of azetidinimines. The first aspect of the present inventionconcerns the identification of azetidinimines which present antibioticproperties, or at least are inhibitors of β-lactamases, morespecifically inhibitors of carbapenemases.

However to obtain a broad array of such compounds, it was necessary todevelop complementary synthesis methods to those of the prior art, whichindeed do not enable to obtain all the desired compounds. The synthesisof these moieties has already been the subject matter of several studyreports developed in particular by the team of Ghosez in the 1980 is(Van Camp, A., Goossens, D., Moya-Portuguez, M., Marchand-Brynaert, J.,Ghosez, L. Tetrahedron Lett. 1980, 21, 3081-3084). Although it was thenadvanced that such structures could be treated as β-lactams, this hadnever been actually verified or even effectively witnessed. Moreover,using these molecules as “suicide molecules” is not disclosed or evensuggested in this document.

The method of Ghosez et al. consists in the following:

The main issue raised by the process of Ghosez et al. is the necessityto generate a sufficiently electrophile cetenimine, which is for thispurpose tosylated (“Ts”), in order to obtain the four membered ringazetidinimine. The nature of the azetidinimine is thus limited throughthis method.

Other ways to synthesize azetidinimine were reported later-on, such asthe first cycloaddition [2+2] involving an intramolecular iminoceteneand imine reported by the research team of Alajardin (Alajardin, M.,Molina, P., Vidal, A. Tetrahedron Lett. 1996, 37, 8945-8948.). It isreported that the driving force of this reaction is probably theformation of a ring system involving two closely hindered reactants.

Multicomponent azetidinimides synthesis was also studied by severalteams such as the team of Folkin and more recently Shanmugam or Lu. Itwas showed that it was possible to access the desired compounds byreacting an alkyne, an azide substituted with an electron-withdrawinggroup and an imine in the presence of a complex copper (I) and a base(triethylamine or pyridine):

Although applicable for the purposes of the present invention, thepreparation of azetidinimines is scarce in the literature. Also,following the examples known in the literature as explained above, inview of work done at the laboratory, another original way of access wasconsidered.

Indeed, it was observed the formation of an amidine by performing anaddition on the indole α position of a ynamide in the presence of sodiumtert-butoxide (Hentz, A., Retailleau, P., Gandon, V.; Cariou, K., Dodd,R. H Angew. Chem. Int. Ed., 2014, 53, 8333-8337):

A mechanism of the reaction was then advanced. A yet unproved hypothesiswas that the base at the same time deprotonates the indole whilstunprotecting the ynamide, which then leads to its tautomeric form beforebeing trapped by the indolate just formed. It was then supposed that asecond tautomerization could then lead to the final product:

Such hypothesis allows the formation of a nitrogen unprotectediminocetene intermediate. Considering the prior art for the preparationof the intramolecular azetidinimines mentioned above, it seemsreasonable to test this theory by adding a nucleophilic species to suchintermediaries in order to obtain four-membered ring azetidimineswherein the exterior nitrogen would be unprotected:

Although not all experimental conditions enabled to obtain suchproducts, the advanced initial theory, which was unobvious by means,seems to have been proved, in particular experimental conditions thusenabling to provide new ways to obtain the sought compounds according tothe present invention. These specific conditions comprise at least abase, an ynamide and an imine.

SUMMARY OF THE INVENTION

The subject matter of the present invention thus concerns a compound offormula (I):

characterized in that:

-   -   R₁ represents a chemical moiety chosen in the group consisting        of hydrogen, cyano, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀        alkoxy, C₁-C₁₀ haloalkoxy, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl,        (C₁-C₆)-haloalkoxy-(C₁-C₆)-alkyl, C₁-C₁₀ thioalkyl,        (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₁₀ alkylsulfinyl, C₁-C₁₀        haloalkylsulfinyl, C₁-C₁₀ haloalkylsulfonyl, C₃-C₁₀        trialkylsilyl, C₁-C₁₀ alkylsulfonyl, C₅-C₁₂ arylsulfonyl,        formyl, C₂-C₁₀ alkylcarbonyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,        C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy, C₂-C₁₀ alkenylthio, C₂-C₁₀        alkynylthio, C₁-C₁₀ haloalkyl, C₂-C₁₀ haloalkenyl, C₂-C₁₀        haloalkynyl, C₂-C₁₀ haloalkylcarbonyl, C₁-C₁₀ haloalkylthio,        C₂-C₁₀ haloalkenyloxy, C₂-C₁₀ haloalkynyloxy, C₂-C₁₀        haloalkenylthio, C₂-C₁₀ haloalkynylthio,        (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl, (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl ester        or a mono or polycyclic C₅-C₁₂ aryl or mono or polycyclic C₃-C₁₂        heteroaryl fragments, wherein the aryl or heteroaryl fragments        are optionally substituted by one or several halogen atoms,        nitro, cyano, formyl, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,        amino-C₁-C₁₀ alkoxy, (carboxylic acid)-C₁-C₁₀ alkoxy, (1,2        diol)-C₂-C₁₀ alkoxy, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, C₂-C₆        alkylcarbonyl, C₁-C₆ alkylthio, C₁-C₆ thioalkyl,        (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆        alkylsulfonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆        haloalkoxy alkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio,        C₁-C₆ haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆        trialkylsilyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl,        C₂-C₆ haloalkenyl, C₂-C₆ haloalkenyloxy, C₂-C₆ haloalkynyloxy,        C₂-C₆ alkenyloxy, C₂-C₆ alkynyloxy, C₂-C₆ alkenylthio, C₂-C₆        alkynylthio, C₂-C₆ haloalkenylthio, C₂-C₆ haloalkynylthio and/or        nitro fragments,    -   R₂, R₃, R₄ and R₅, independently one from each other, represent        a chemical moiety chosen in the group consisting of hydrogen,        halogen, nitro, cyano, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀        alkoxy, C₁-C₁₀ haloalkoxy, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl,        (C₁-C₆)-haloalkoxy-(C₁-C₆)-alkyl, C₁-C₁₀ thioalkyl,        (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl ester,        (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₁₀ alkylsulfinyl, C₁-C₁₀        haloalkylsulfinyl, C₁-C₁₀ haloalkylsulfonyl, C₃-C₁₀        trialkylsilyl, C₁-C₁₀ alkylsulfonyl, C₅-C₁₂ arylsulfonyl,        formyl, C₂-C₁₀ alkylcarbonyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,        C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy, C₂-C₁₀ alkenylthio, C₂-C₁₀        alkynylthio, C₁-C₁₀ haloalkyl, C₂-C₁₀ haloalkenyl, C₂-C₁₀        haloalkynyl, C₂-C₁₀ haloalkylcarbonyl, C₁-C₁₀ haloalkylthio,        C₂-C₁₀ haloalkenyloxy, C₂-C₁₀ haloalkynyloxy, C₂-C₁₀        haloalkenylthio, C₂-C₁₀ haloalkynylthio,        (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl or a mono or polycyclic C₅-C₁₂ aryl        or mono or polycyclic C₃-C₁₂ heteroaryl fragments, wherein the        aryl or heteroaryl fragments are optionally substituted by one        or several halogen atoms, nitro, cyano, formyl, C₁-C₆ alkyl,        C₃-C₇ cycloalkyl, C₁-C₆ alkoxy, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl,        C₂-C₆ alkylcarbonyl, C₁-C₆ alkylthio, C₁-C₆ thioalkyl,        (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆        alkylsulfonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆        haloalkoxy alkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio,        C₁-C₆ haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆        trialkylsilyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl,        C₂-C₆ haloalkenyl, C₂-C₆ haloalkenyloxy, C₂-C₆ haloalkynyloxy,        C₂-C₆ alkenyloxy, C₂-C₆ alkynyloxy, C₂-C₆ alkenylthio, C₂-C₆        alkynylthio, C₂-C₆ haloalkenylthio, C₂-C₆ haloalkynylthio and/or        nitro fragments;    -   R₆ represents a chemical moiety chosen in the group consisting        of hydrogen, halogen, nitro, cyano, C₁-C₁₀ alkyl, C₃-C₁₀        cycloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkoxy,        (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, (C₁-C₆)-haloalkoxy-(C₁-C₆)-alkyl,        C₁-C₁₀ thioalkyl, (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₁₀        alkylsulfinyl, C₁-C₁₀ haloalkylsulfinyl, C₁-C₁₀        haloalkylsulfonyl, C₃-C₁₀ trialkylsilyl, C₁-C₁₀ alkylsulfonyl,        C₅-C₁₂ arylsulfonyl, formyl, C₂-C₁₀ alkylcarbonyl, C₂-C₁₀        alkenyl, C₂-C₁₀ alkynyl, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,        C₂-C₁₀ alkenylthio, C₂-C₁₀ alkynylthio, C₁-C₁₀ haloalkyl, C₂-C₁₀        haloalkenyl, C₂-C₁₀ haloalkynyl, C₂-C₁₀ haloalkylcarbonyl,        C₁-C₁₀ haloalkylthio, C₂-C₁₀ haloalkenyloxy, C₂-C₁₀        haloalkynyloxy, C₂-C₁₀ haloalkenylthio, C₂-C₁₀ haloalkynylthio,        (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl or a mono or polycyclic C₅-C₁₂ aryl        or mono or polycyclic C₃-C₁₂ heteroaryl fragments, wherein the        aryl or heteroaryl fragments are optionally substituted by one        or several halogen atoms, nitro, cyano, formyl, C₁-C₆ alkyl,        C₃-C₇ cycloalkyl, C₁-C₆ alkoxy, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl,        C₂-C₆ alkylcarbonyl, C₁-C₆ alkylthio, C₁-C₆ thioalkyl,        (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₆alkylsulfinyl, C₁-C₆        alkylsulfonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆        haloalkoxy alkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio,        C₁-C₆ haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆        trialkylsilyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl,        C₂-C₆ haloalkenyl, C₂-C₆ haloalkenyloxy, C₂-C₆ haloalkynyloxy,        C₂-C₆ alkenyloxy, C₂-C₆ alkynyloxy, C₂-C₆ alkenylthio, C₂-C₆        alkynylthio, C₂-C₆ haloalkenylthio, C₂-C₆ haloalkynylthio and/or        nitro fragments;        to the condition that:    -   R₆ is not a substituted or unsubstituted —SO₂-phenyl group such        as a tosyl group;    -   when R₆ is a hydrogen atom:    -   R₅ and R₄ cannot be methyls, R₃ and R₁ cannot be phenyls and, R₂        cannot be a hydrogen atom;    -   R₅ and R₂ cannot be hydrogen atoms and R₄, R₃ and R₁ cannot be        phenyls;    -   R₅, R₃, R₁ cannot be phenyls and, R₄ and R₂ cannot be hydrogen        atoms;    -   when R₆ is a methyl:    -   R₅ and R₄ cannot be methyls, R₃ and R₁ cannot be phenyls and, R₂        cannot be a hydrogen atom;    -   R₅ and R₂ cannot be hydrogen atoms and R₄, R₃ and R₁ cannot be        phenyls;    -   when R₆ is —SO₂-Me:    -   R₅, R₃ and R₁ cannot be phenyls, R₄ and R₂ cannot be hydrogen        atoms; and    -   when R₆ is a cyano:    -   the couple (R₅ and R₄) cannot be a methyl and a hydrogen atom,        the couple (R₂ and R₃) cannot be phenyl and a hydrogen atom, and        R₁ cannot be phenyl.

The subject matter of the present invention further concerns a compoundof formula (I) above characterized in that:

-   -   R₁ represents a chemical moiety chosen in the group consisting        of hydrogen, cyano, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀        alkoxy, C₁-C₁₀ haloalkoxy, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl,        (C₁-C₆)-haloalkoxy-(C₁-C₆)-alkyl, C₁-C₁₀ thioalkyl,        (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₁₀ alkylsulfinyl, C₁-C₁₀        haloalkylsulfinyl, C₁-C₁₀ haloalkylsulfonyl, C₃-C₁₀        trialkylsilyl, C₁-C₁₀ alkylsulfonyl, C₅-C₁₂ arylsulfonyl,        formyl, C₂-C₁₀ alkylcarbonyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,        C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy, C₂-C₁₀ alkenylthio, C₂-C₁₀        alkynylthio, C₁-C₁₀ haloalkyl, C₂-C₁₀ haloalkenyl, C₂-C₁₀        haloalkynyl, C₂-C₁₀ haloalkylcarbonyl, C₁-C₁₀ haloalkylthio,        C₂-C₁₀ haloalkenyloxy, C₂-C₁₀ haloalkynyloxy, C₂-C₁₀        haloalkenylthio, C₂-C₁₀ haloalkynylthio,        (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl, (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl ester        or a mono or polycyclic C₅-C₁₂ aryl or mono or polycyclic C₃-C₁₂        heteroaryl fragments,    -   wherein the aryl or heteroaryl fragments are optionally        substituted by        -   one or several halogen atoms, hydroxyl (OH), nitro, cyano,            formyl, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, amino-C₁-C₁₀ alkoxy,            (carboxylic acid)-C₁-C₁₀ alkoxy, (carboxylic (C₁-C₆)alkyl            ester)-C₁-C₁₀ alkoxy, (1,2 diol)-C₂-C₁₀ alkoxy,            —O—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-OH,            (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, C₂-C₆ alkylcarbonyl, C₁-C₆            alkylthio, C₂-C₆ thioalkyl, (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl,            C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkyl,            C₁-C₆ haloalkoxy, C₁-C₆ haloalkoxy alkyl, C₂-C₆            haloalkylcarbonyl, C₁-C₆ haloalkylthio, C₁-C₆            haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆            trialkylsilyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₂-C₆            haloalkynyl, C₂-C₆ haloalkenyl, C₂-C₆ haloalkenyloxy, C₂-C₆            haloalkynyloxy, C₂-C₆ alkenyloxy, C₂-C₆ alkynyloxy, C₂-C₆            alkenylthio, C₂-C₆ alkynylthio, C₂-C₆ haloalkenylthio, C₂-C₆            haloalkynylthio, and/or a C₁-C₆ alkoxy optionally            substituted by a mono or polycyclic C₅-C₁₂ aryl group,            and/or        -   a bridging group of formula —O—CH₂—O— or —O—CH₂CH₂—O—;    -   R₂, R₃, R₄ and R₅, independently one from each other, represent        a chemical moiety chosen in the group consisting of hydrogen,        halogen, nitro, cyano, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl, C₁-C₁₀        alkoxy, C₁-C₁₀ haloalkoxy, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl,        (C₁-C₆)-haloalkoxy-(C₁-C₆)-alkyl, C₁-C₁₀ thioalkyl,        (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl ester,        (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₁₀ alkylsulfinyl, C₁-C₁₀        haloalkylsulfinyl, C₁-C₁₀ haloalkylsulfonyl, C₃-C₁₀        trialkylsilyl, C₁-C₁₀ alkylsulfonyl, C₅-C₁₂ arylsulfonyl,        formyl, C₂-C₁₀ alkylcarbonyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,        C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy, C₂-C₁₀ alkenylthio, C₂-C₁₀        alkynylthio, C₁-C₁₀ haloalkyl, C₂-C₁₀ haloalkenyl, C₂-C₁₀        haloalkynyl, C₂-C₁₀ haloalkylcarbonyl, C₁-C₁₀ haloalkylthio,        C₂-C₁₀ haloalkenyloxy, C₂-C₁₀ haloalkynyloxy, C₂-C₁₀        haloalkenylthio, C₂-C₁₀ haloalkynylthio,        (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl or a mono or polycyclic C₅-C₁₂ aryl        or mono or polycyclic C₃-C₁₂ heteroaryl fragments, wherein the        aryl or heteroaryl fragments are optionally substituted by one        or several halogen atoms, nitro, cyano, formyl, COOH, —COO(C₁-C₆        alkyl), C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ N₃-substituted        alkyl, C₁-C₆ NH₂-substituted alkyl, C₁-C₆ alcohol, C₁-C₆ alkoxy,        (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, C₂-C₆ alkylcarbonyl, C₁-C₆        alkylthio, C₁-C₆ thioalkyl, (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl,        C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkyl, C₁-C₆        haloalkoxy, C₁-C₆ haloalkoxy alkyl, C₂-C₆ haloalkylcarbonyl,        C₁-C₆ haloalkylthio, C₁-C₆ haloalkylsulfinyl, C₁-C₆        haloalkylsulfonyl, C₃-C₆ trialkylsilyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₂-C₆ haloalkynyl, C₂-C₆ haloalkenyl, C₂-C₆        haloalkenyloxy, C₂-C₆ haloalkynyloxy, C₂-C₆ alkenyloxy, C₂-C₆        alkynyloxy, C₂-C₆ alkenylthio, C₂-C₆ alkynylthio, C₂-C₆        haloalkenylthio, C₂-C₆ haloalkynylthio, a monocyclic C₅-C₆ aryl        group optionally substituted by a C₁-C₆ alkyloxy group, and/or a        COO(C₁-C₆ alkyl) group wherein the alkyl is substituted by NH₂        or NHCOO(C₁-C₆)alkyl or NHCOO(C₁-C₆)alkyl(mono or polycyclic        C₅-C₁₂)aryl;    -   R₆ represents a mono or polycyclic C₅-C₁₂ aryl fragment, wherein        the aryl fragment is optionally substituted by one or several        halogen atoms, cyano, nitro formyl, C₁-C₆ alkyl, C₃-C₇        cycloalkyl, C₁-C₆ alkoxy, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, C₂-C₆        alkylcarbonyl, C₁-C₆ alkylthio, C₁-C₆ thioalkyl,        (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₆alkylsulfinyl, C₁-C₆        alkylsulfonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆        haloalkoxy alkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio,        C₁-C₆ haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆        trialkylsilyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl,        C₂-C₆ haloalkenyl, C₂-C₆ haloalkenyloxy, C₂-C₆ haloalkynyloxy,        C₂-C₆ alkenyloxy, C₂-C₆ alkynyloxy, C₂-C₆ alkenylthio, C₂-C₆        alkynylthio, C₂-C₆ haloalkenylthio, C₂-C₆ haloalkynylthio        fragments and/or a monocyclic C₅-C₆ aryl group optionally        substituted by a C₁-C₆ alkyloxy group;        provided that at least two of R₃, R₄ and R₅ represent a hydrogen        atom and R₆ is not a substituted or unsubstituted —SO₂-phenyl        group such as a tosyl group. The subject matter of the present        invention further concerns a compound of formula (I) above        characterized in that:    -   R₁ represents a chemical moiety chosen in the group consisting        of a mono or polycyclic C₅-C₁₂ aryl or mono or polycyclic C₃-C₁₂        heteroaryl fragments, wherein the aryl or heteroaryl fragments        are optionally substituted by        -   one or several halogen atoms, hydroxyl (OH), nitro, cyano,            formyl, C₁-C₆ alkyl, O₃—C₇ cycloalkyl, amino-C₁-C₁₀ alkoxy,            (carboxylic acid)-C₁-C₁₀ alkoxy, (carboxylic (C₁-C₆)alkyl            ester)-C₁-C₁₀ alkoxy, (1,2 diol)-C₂-C₁₀ alkoxy,            —O—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-OH,            (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, C₂-C₆ alkylcarbonyl, C₁-C₆            alkylthio, C₁-C₆ thioalkyl, (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl,            C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkyl,            C₁-C₆ haloalkoxy, C₁-C₆ haloalkoxy alkyl, C₂-C₆            haloalkylcarbonyl, C₁-C₆ haloalkylthio, C₁-C₆            haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆            trialkylsilyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₂-C₆            haloalkynyl, C₂-C₆ haloalkenyl, C₂-C₆ haloalkenyloxy, C₂-C₆            haloalkynyloxy, C₂-C₆ alkenyloxy, C₂-C₆ alkynyloxy, C₂-C₆            alkenylthio, C₂-C₆ alkynylthio, C₂-C₆ haloalkenylthio, C₂-C₆            haloalkynylthio and/or a C₁-C₆ alkoxy optionally substituted            by a mono or polycyclic C₅-C₁₂ aryl group, and/or        -   a bridging group of formula —O—CH₂—O— or —O—CH₂CH₂—O—;    -   R₂, R₃, R₄ and R₅, independently one from each other, represent        a chemical moiety chosen in the group consisting of a mono or        polycyclic C₅-C₁₂ aryl or mono or polycyclic C₃-C₁₂ heteroaryl        fragments, wherein the aryl or heteroaryl fragments are        optionally substituted by one or several halogen atoms, nitro,        cyano, formyl, COOH, —COO(C₁-C₆ alkyl), C₁-C₆ alkyl, C₃-C₇        cycloalkyl, C₁-C₆ N₃-substituted alkyl, C₁-C₆ NH₂-substituted        alkyl, C₁-C₆ alcohol, C₁-C₆ alkoxy,        (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, C₂-C₆ alkylcarbonyl, C₁-C₆        alkylthio, C₁-C₆ thioalkyl, (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl,        C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkyl, C₁-C₆        haloalkoxy, C₁-C₆ haloalkoxy alkyl, C₂-C₆ haloalkylcarbonyl,        C₁-C₆ haloalkylthio, C₁-C₆ haloalkylsulfinyl, C₁-C₆        haloalkylsulfonyl, C₃-C₆ trialkylsilyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₂-C₆ haloalkynyl, C₂-C₆ haloalkenyl, C₂-C₆        haloalkenyloxy, C₂-C₆ haloalkynyloxy, C₂-C₆ alkenyloxy, C₂-C₆        alkynyloxy, C₂-C₆ alkenylthio, C₂-C₆ alkynylthio, C₂-C₆        haloalkenylthio, C₂-C₆ haloalkynylthio, a monocyclic C₅-C₆ aryl        group optionally substituted by a C₁-C₆ alkyloxy group and/or a        COO(C₁-C₆ alkyl) group wherein the alkyl is substituted by NH₂        or NHCOO(C₁-C₆)alkyl or NHCOO(C₁-C₆)alkyl(mono or polycyclic        C₅-C₁₂)aryl;    -   R₆ represents a mono or polycyclic C₅-C₁₂ aryl or heteroaryl        fragment, wherein the aryl or heteroaryl fragment is optionally        substituted by one or several halogen atoms, cyano, nitro,        formyl, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ alkoxy,        (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, C₂-C₆ alkylcarbonyl, C₁-C₆        alkylthio, C₁-C₆ thioalkyl, (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl,        C₁-C₆alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkyl, C₁-C₆        haloalkoxy, C₁-C₆ haloalkoxy alkyl, C₂-C₆ haloalkylcarbonyl,        C₁-C₆ haloalkylthio, C₁-C₆ haloalkylsulfinyl, C₁-C₆        haloalkylsulfonyl, C₃-C₆ trialkylsilyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₂-C₆ haloalkynyl, C₂-C₆ haloalkenyl, C₂-C₆        haloalkenyloxy, C₂-C₆ haloalkynyloxy, C₂-C₆ alkenyloxy, C₂-C₆        alkynyloxy, C₂-C₆ alkenylthio, C₂-C₆ alkynylthio, C₂-C₆        haloalkenylthio, C₂-C₆ haloalkynylthio fragments and/or a        monocyclic C₅-C₆ aryl group optionally substituted by a C₁-C₆        alkyloxy group;    -   provided that at least two of R₃, R₄ and R₅ represent a hydrogen        atom and R₆ is not a substituted or unsubstituted —SO₂-phenyl        group such as a tosyl group.

The subject matter of the present invention also concerns a method toprepare a compound of formula (I) above, however including theexplicitly excluded compounds above, characterized in the followingsteps:

-   -   a. to a compound of formula (II):

-   -   wherein R₄ and R₆ are as defined presently, including the        excluded definitions above, and R₇ represents a leaving group        such as amides, sulfonyles, or oxy-carbonyls,    -   optionally, R₆—N—R₇ may form at least one ring wherein R₆ and R₇        directly linked one to each other and wherein said ring        comprises from 3 to 12 atoms chosen from C, N, O, S, B and P        (preferably chosen from C, N, O, S and B, even more preferably        from C, N, O and S), substituted by at least one hydrogen,        oxygen, nitrogen, hydroxyl, thiol, amine, cyano, C₁-C₆ alkyl,        C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,        (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, (C₁-C₆)-haloalkoxy-(C₁-C₆)-alkyl,        C₁-C₆ thioalkyl, (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₆        alkylsulfinyl, C₁-C₆ haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl,        C₃-C₆ trialkylsilyl, C₁-C₆ alkylsulfonyl, C₅-C₁₂ arylsulfonyl,        formyl, C₂-C₆ alkylcarbonyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₂-C₆        alkenyloxy, C₂-C₆ alkynyloxy, C₂-C₆ alkenylthio, C₂-C₆        alkynylthio, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl, C₂-C₆        haloalkynyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio, C₂-C₆        haloalkenyloxy, C₂-C₆ haloalkynyloxy, C₂-C₆ haloalkenylthio,        C₂-C₆ haloalkynylthio, (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl or a mono or        polycyclic C₅-C₁₂ aryl or mono or polycyclic C₃-C₁₂ heteroaryl        fragments, wherein the aryl or heteroaryl fragments are        optionally substituted by one or several halogen atoms, nitro,        cyano, formyl, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ alkoxy,        (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, C₂-C₆ alkylcarbonyl, C₁-C₆        alkylthio, C₁-C₆ thioalkyl, (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl,        C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkyl, C₁-C₆        haloalkoxy, C₁-C₆ haloalkoxy alkyl, C₂-C₆ haloalkylcarbonyl,        C₁-C₆ haloalkylthio, C₁-C₆ haloalkylsulfinyl, C₁-C₆        haloalkylsulfonyl, C₃-C₆ trialkylsilyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₂-C₆ haloalkynyl, C₂-C₆ haloalkenyl, C₂-C₆        haloalkenyloxy, C₂-C₆ haloalkynyloxy, C₂-C₆ alkenyloxy, C₂-C₆        alkynyloxy, C₂-C₆ alkenylthio, C₂-C₆ alkynylthio, C₂-C₆        haloalkenylthio, C₂-C₆ haloalkynylthio and/or nitro fragments;    -   is added a compound of formula (III):

-   -   wherein R₁, R₂ and R₃ are as defined presently    -   in the presence of a base B1, preferably R₁ is an        electro-donating group and/or R₂ and/or R₃ are        electron-withdrawing groups,    -   preferably under microwaves;    -   b. an optional addition step of R₅, and/or R₄, as defined above        for compound of formula (I) presently through a nucleophilic        addition to the compound obtained in step (a), preferably with        R₅—X, and/or R₄—X, wherein X is a halogen atom in the presence        of a base B2;    -   c. retrieving the compound of formula (I) as defined presently.

The subject matter of the present invention also concerns a compound offormula (II) above as such, preferably as a synthesis intermediate orits equivalent carbene.

The subject matter of the present invention moreover concerns a compoundof formula (I) as defined presently, including the explicitly excludedcompounds above, as a drug.

The subject matter of the present invention furthermore concerns a useof a compound of formula (I) as defined presently including theexplicitly excluded compounds above, as an inhibitor of a carbapenemaseenzyme, preferably of a NDM-1 type, OXA-48 type or a KPC-type enzymes.The present invention further concerns a compound of formula (I) asdefined presently including the explicitly excluded compounds above, firuse as an inhibitor of a carbapenemase enzyme, preferably of a NDM-1type, OXA-48 type or a KPC-type enzymes.

Accordingly, the subject matter of the present invention concerns acompound of formula (I) as defined presently including the explicitlyexcluded compounds above, for its use as an antibiotic.

The subject matter of the present invention concerns a compound offormula (I) as defined presently including the explicitly excludedcompounds above for its use in combination with an antibiotic.

Definitions

Generally speaking in the context of the present invention, unlessspecified differently, the expression “a compound of formula (I)” meansany one of all variants of formula (I), including the excluded compoundsabove.

As customary in the art, in the present invention, “Me” stands formethyl (—CH₃), Bn stands for benzyl (—CH₂—C₆H₅) and Ph stands for phenyl(—C₆H₅).

The expressions “C₁-C₁₀ alkyl”/“alkyl” (i.e. the number of carbons in“alkyl” are not explicitly given) in the present invention mean acyclic, linear or branched saturated aliphatic group with 1 to 10 carbonatoms if not otherwise specified. An alkyl group covered by the scope ofthe present invention is for example a group chosen from methyl, ethyl,propyl, butyl, tert-butyl, isopropyl, cyclopropyl, etc.

The expressions “C₃-C₁₀ cycloalkyl”/“cycloalkyl” (i.e. the number ofcarbons in “cycloalkyl” are not explicitly given) in the presentinvention mean a cyclic alkyl group with 3 to 10 carbon atoms if nototherwise specified. A cycloalkyl group covered by the scope of thepresent invention is for example a group chosen from cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, etc.

The expression “C₁-C₁₀ thioalkyl” in the present invention means aC₁-C₁₀ alkyl moiety as presently defined, substituted by a thiol group,i.e. SH or a salt thereof.

The expression “C₁-C₆ alkylthio” in the present invention represents a“(C₁-C₆ alkyl)-S—” group, i.e. an alkyl moiety with 1 to 6 carbon atoms,if not otherwise specified, as defined above linked to the rest of themolecule by a sulfur atom.

The expression “(C₁-C₆)-alkylthio-(C₁-C₆)-alkyl” in the presentinvention represents a “(C₁-C₆)-alkylthio” as presently defined linkedby its sulfur atom to any carbon atom of a “C₁-C₆ alkyl” as definedpresently.

The expressions “C₁-C₁₀ alkoxy”/“C₁-C₁₀ alkyloxy” represent a “(C₁-C₆alkyl)-O—” group, i.e. an alkyl moiety with 1 to 10 carbon atoms, if nototherwise specified, as defined above, linked to the rest of themolecule by an oxygen atom. Examples of alkoxy groups covered by thescope of the present invention are methoxy, ethoxy groups etc.

The expression “(1,2 diol)-C₂-C₁₀ alkoxy” in the present inventionrepresents an alkoxy group as defined above, wherein two adjacent carbonatoms are each linked to a hydroxyl group. The “1,2” does not limit theposition to the first and second carbon atom attached to the rest of themolecule. Indeed, it is meant in the general context of the presentinvention that the hydroxyl groups are linked to two adjacent carbon,such as in position 2,3; 3,4; 4,5 . . . i.e. “n, n+1” wherein n is theposition on the alkyl moiety, and thus n+1 cannot be superior to thetotal number of carbon atoms.

The expression “(carboxylic acid)-C₁-C₁₀ alkoxy” in the presentinvention represents an alkoxy group as defined above, wherein at leastone carbon atom is linked to a fragment “COOH”, “COO⁻” or a saltthereof. Preferably, the “COOH” or “COO—” group or salt thereof islinked to the last carbon of the main linear chain of said C₁-C₁₀ alkoxygroup.

The expression “(carboxylic (C₁-C₆)alkyl ester)-C₁-C₁₀ alkoxy” in thepresent invention represents an alkoxy group as defined above, whereinat least one carbon atom is linked to a carboxylic ester group offormula —COO—(C₁-C₆)alkyl, through the carboxylic group. Preferably, thecarboxylic ester group is linked to the last carbon of the main linearchain of said C₁-C₁₀ alkoxy group.

The expression “C₁-C₆ N₃-substituted alkyl” in the present inventionrepresents an alkyl group as defined above, wherein at least one carbonatom is substituted by a N₃ group. Preferably, the N₃ group is linked tothe last carbon of the main linear chain of said C₁-C₆ alkyl group.

The expression “C₁-C₆ NH₂-substituted alkyl” in the present inventionrepresents an alkyl group as defined above, wherein at least one carbonatom is substituted by an amino (NH₂) group. Preferably, the N₃ group islinked to the last carbon of the main linear chain of said C₁-C₆ alkylgroup.

The expression “C₁-C₁₀ alkylsulfinyl” in the present inventionrepresents a “(C₁-C₁₀ alkyl)-S(═O)—”, i.e. an alkyl moiety of 1 to 10carbon atoms, if not otherwise specified, as defined above, linked tothe rest of the molecule by a sulphur atom which is mono oxidised.

The expression “C₁-C₁₀ alkylsulfonyl” in the present inventionrepresents a “(C₁-C₁₀ alkyl)-S(═O)₂—”, i.e. an alkyl moiety of 1 to 10carbon atoms, if not otherwise specified, as defined above, linked tothe rest of the molecule by a sulphur atom which is oxidised twice.

The expression “(C₁-C₆)-alkoxy-(C₁-C₆)-alkyl” in the present inventionrepresents a “(C₁-C₆)-alkoxy” as defined above linked by its oxygen atomto any carbon atom of a “C₁-C₆ alkyl” group as defined above, the latteralkyl moiety being linked to the rest of the molecule.

The term “formyl” in the present invention represents a H—C(═O)— group.

The expression “C₂-C₁₀ alkylcarbonyl” in the present invention means analkyl group as presently defined linked to a carbonyl, the carbonylbeing itself linked to the rest of the molecule (e.g. of formula (I)).

The expression “C₃-C₁₀ trialkylsilyl” in the present invention meansthat three alkyl groups as defined above linked to one Si atom, thetotal number of carbon atoms amounting to 3 up to 10, said alkyl groupsbeing itself being linked to the rest of the molecule.

The expressions “C₅-C₁₂ aryl”/“aryl” (i.e. the number of carbons in“aryl” are not explicitly given) in the present invention mean a cyclic(mono- or polycyclic) aromatic group comprising between 5 and 12 carbonatoms if not otherwise specified. Examples of aryl groups covered by thescope of the present invention are phenyl, naphthyl, etc.

The expression “monocyclic C₅-C₁₂ aryl” in the present inventionrepresents an aryl fragment as defined here-above with only onehydrocarbon ring such as a phenyl fragment.

The expression “polycyclic C₅-C₁₂ aryl” in the present inventionrepresents an aryl fragment as defined above with more than onehydrocarbon ring such as a naphtalene, anthracene, or a phenanthrenefragment.

The expression “heteroaryl” in the present invention means a cyclic(mono- or polycyclic) aromatic group comprising between 5 and 12 atomswhich can be carbon atoms and/or heteroatoms such as nitrogen, oxygen orsulphur (e.g. the heteroaryl can comprise between 3 to 9 carbon atomsand between 1 and 5 heteroatoms). Examples of heteroaryl groups coveredby the scope of the present invention are pyridine, thiophene, thiazole,imidazole, pyrazole, pyrrole, quinoline, indole, pyridazine,quinoxaline, dihydrobenzofuran etc.

The expression “monocyclic C₅-C₁₂ heteroaryl” in the present inventionrepresents a heteroaryl fragment as defined here-above with only onemulti-atom ring such as a pyridyl, thiazole, imidazole, etc. fragment.

The expression “polycyclic C₅-C₁₂ heteroaryl” in the present inventionrepresents a heteroaryl fragment as defined above with more than onemulti-atom ring such as a quinoline, indole, quinoxaline, etc. fragment.

As used herein, an “aryl or heteroaryl substituted by a bridging group”is understood as an aryl or heteroaryl group wherein the bridging groupsubstitutes two carbons of the aryl or heteroaryl, and forms togetherwith said aryl or heteroaryl a fused polycyclic group. For instance, ifthe aryl or heteroaryl is monocyclic, then said monocyclic aryl orheteroaryl substituted by a bridging group is a fused bicyclic group. Ingeneral, the bridging group substitutes two adjacent atom on the aryl(or heteroaryl) group. Examples of such aryl or heteroaryl substitutedby a bridging group include 1,3-benzodioxole and 1,4-benzodioxane.

The expression “(C₅-C₁₂)-aryl-(C₁-C₆)-alkyl” in the present inventionrepresents a “(C₅-C₁₂)-aryl” as defined above linked to any carbon atomof a “C₁-C₆ alkyl” group as defined above, the alkyl moiety being linkedto the rest of the molecule.

The expression “C₅-C₁₂ arylsulfonyl” in the present invention representsa “(C₅-C₁₂ aryl)-S(═O)₂—”, i.e. an aryl moiety of 5 to 12 carbon atomsas defined above linked to a sulphur atom which is oxidised twice.

The expressions “C₂-C₁₀ alkenyl”/“alkenyl” (i.e. the number of carbonsin “alkenyl” are not explicitly given) in the present invention mean acyclic, linear or branched aliphatic group with 2 to 10 carbon atoms, ifnot otherwise specified, comprising at least one unsaturation, i.e. atleast one double bond. An alkenyl group covered by the scope of thepresent invention is for example a group chosen from ethylene,propyl-1-ene, propyl-2-ene, butyl-1-ene, butyl-2-ene, etc.

The expression “C₂-C₁₀ alkenylthio” in the present invention representsa “(C₂-C₁₀ alkenyl)-S—”, i.e. an alkenyl moiety of 2 to 10 carbon atoms,if not otherwise specified, as defined above linked to the rest of themolecule by a sulfur atom.

The expression “C₂-C₁₀ alkenyloxy”, in the present invention representsa “(C₁-C₆ alkenyl)-O—” group, i.e. an alkenyl moiety with 2 to 10 carbonatoms, if not otherwise specified, as defined above, linked to the restof the molecule by an oxygen atom. Examples of alkenyloxy groups coveredby the scope of the present invention are ethylenoxy, propyl-1-enoxygroups etc.

The expressions “C₂-C₁₀ alkynyl”/“alkynyl” (i.e. the number of carbonsin “alkynyl” are not explicitly given) in the present invention mean acyclic, linear or branched aliphatic group with 2 to 10 carbon atoms, ifnot otherwise specified, comprising at least one double in saturation,i.e. at least one triple bond. Examples of alkenyl groups covered by thescope of the present invention are acetylene, propyl-1-yne,propyl-2-yne, butyl-1-yne, butyl-2-yne, etc.

The expression “C₂-C₁₀ alkynyloxy”, in the present invention means analkynyl group defined above bound to an oxygen atom. Examples ofalkynyloxy groups covered by the scope of the present invention areacetylenoxy, propyn-1-yloxy groups etc.

The expression “C₂-C₁₀ alkynylthio” in the present invention representsa “(C₂-C₆₁₀ alkynyl)-S—”, i.e. an alkynyl moiety of 2 to 10 carbonatoms, if not otherwise specified, as defined above linked to the restof the molecule by a sulfur atom.

The expression “halogen atom” (equivalent to “halo” when used) in thepresent invention means at least one atom of fluorine, chlorine, bromineor iodine. For example a C₁-C₁₀ haloalkyl is an alkyl as presentlydefined substituted by at least one halogen atom. Examples of C₁-C₁₀haloalkyl are —CH₂F₁, —CHF₂—, —CF₃, —CH₂Cl₁, —CHCl₂—, —CCl₃, —CH₂Br₁,—CHBr₂—, —CBr₃, —CH₂I₁, —CHI₂—, —Cl₃, —CH₂—CH₂F₁, —CH₂—CHF₂—, —CH₂—CF₃,—CFH—CH₃—CF₂—CH₃, etc.

The expression “nitro” in the present invention means a NO₂ group.

Examples of “COO(C₁-C₆ alkyl) group wherein the alkyl is substituted byNH₂ or NHCOO(C₁-C₆)alkyl or NHCOO(C₁-C₆)alkyl(mono or polycyclicC₅-C₁₂)aryl” in the present invention are COOCH₂CH₂NHCOO^(t)Bu,COOCH₂CH₂NHCOO^(t)Bu and COOCH₂CH₂NH₂. Of course, in case of a NH₂substituent, the amine may also be salified, for instance it may be aNH3⁺ X⁻ group, wherein X⁻ represents an organic or inorganic anion witha single charge, such as for instance a halogenide (Cl⁻, Br⁻ or I⁻ inparticular) or a (C₁-C₆)alkyl-COO— or (C₁-C₆)haloalkyl-COO—, inparticular CH₃COO⁻ or CF₃COO⁻.

The expression “leaving group” in the context of the present inventionrepresents a molecular fragment or an atom departing from the moleculeit initially belonged to, with typically a pair of electrons being tornoff said molecule. Such “leaving groups” according to the presentinvention, can be chosen in the group consisting of amides (e.g.acetamide), sulfonyles (e.g. tosylate, mesylates), oxy-carbonyls (i.e.carboxylates), carbamates (e.g. Boc), dinitrogen (N₂ ⁺),perfluoroalkylsulfonates (triflate), halogens (i.e. F, Cl, Br, I),amines, thiolates, phosphates, phenoxides. Preferably the “leavinggroups” of the present invention are chosen in the group consisting ofamides (e.g. acetamide), sulfonyles (e.g. tosylate, mesylates),oxy-carbonyls (i.e. carboxylates), carbamates (e.g. Boc). In aparticular embodiment of the present invention, the leaving group iscomprised in at least one molecular ring formed by R₆—N—R₇ of formula(II). In this latter case, the ring formed can comprise e.g. lactames,oxazolidinone, or even sultames.

An “electron-withdrawing group” (“EWG”) means in the context of thepresent invention that the fragments is an electron attracting fragment,such as para-halogenophenyl, a CF₃, a phenyl, a fragment comprising acarbonyl, a cyano, a 3-pyridyl, a 4-methoxy phenyl, an amide, asulphonamide, a carbamate, a 3,4,5-trimethoxyphenyl, a4-methylthio-phenyl, a 4-ethoxy-phenyl, a 4-iodo-phenyl, a 4-nitrophenyl or a 4-[(2,3 diol)-propoxy]-phenyl fragment, preferably aninductive attracting fragment such as a para-halogenophenyl, a CF₃, aphenyl, a 3-pyridyl, a 4-methoxy phenyl, a 3,4,5-trimethoxyphenyl, a4-methylthio-phenyl, a 4-ethoxy-phenyl, a 4-iodo-phenyl, a 4-nitrophenyl or a 4-[(2,3 diol)-propoxy]-phenyl fragment.

An “electro-donating group” (“EDG”) means in the context of the presentinvention that the fragments is an electron enriching fragment, such asa 4-methoxy phenyl, a 3,4,5-trimethoxyphenyl, a 4-methylthio-phenyl, a4-ethoxy-phenyl, a 4-iodo-phenyl, a 4-nitro phenyl or a 4-[(2,3diol)propoxy]-phenyl fragment.

The term “microwaves” (“MW”) according to the present inventioncomprises any electromagnetic radiation with wavelengths ranging from aslong as a meter to as short to a millimeter, with frequencies between300 MHz and 300 GHz. On a practical point of view, the frequency andother characteristics of the microwaves are adapted to the solvent used.For example, in the case of polar solvents like water, a frequency of2.46 GHz will be used. Thus in the context of the present invention, thefrequency of the MW used is preferably comprised between 1 and 10 GHz,more specifically from 2 to 3 GHz, such as 2.46 Ghz.

The expression “ambient temperature” (“AT”) in the context of thepresent invention means a temperature comprised between 20 and 25° C.

The expression “nucleophilic addition”, represents an addition reactionwhere a chemical compound with an electron-deficient or electrophilicdouble or triple bond, a π bond, reacts with electron-rich reactant,termed a nucleophile, with disappearance of the double bond and creationof two new single, i.e. a, bonds.

The expression “synthesis intermediate”, generally speaking, is amolecular entity that is formed from the reactants (or proceedingintermediates) and reacts further to give the directly observed productsof a chemical reaction. The chemical reactions being stepwise, they takemore than one elementary step to complete. Indeed, one of the aspects ofthe present invention concerns a process wherein e.g. the compound offormula (II) is used as a synthesis intermediate to produce the compoundof formula (I). Moreover, in formula (I) when R₄ and/or R₅ is a hydrogenatom, this formula can be considered as a synthesis intermediate for thecompound of formula (I) wherein R₄ and/or R₅ (which is/are different toa hydrogen) has been introduced through a nucleophilic addition (seestep (b) of the process above).

The expression “carbapenemase enzyme” concerns enzymes of theβ-lactamase type which have the capacity to hydrolyze cephalosporins,monobactams, carbapenems and penicillins. These β-lactamases, inparticular carbapenemase, produced in bacteria are often responsible ofthe ineffectiveness of many β-lactams. Carbapenemase can be subdivisedin A, B and D β-lactamases. Carbapenemase of class A include members ofthe SME, IMI, NMC, GES, and KPC families. The Klebsiella pneumoniaeCarbapenemases (KPC) are the most prevalent, found mostly on plasmids(of Klebsiella pneumoniae). Carbapenemase of class D consist of OXA-typeβ-lactamases frequently detected in Acinetobacter baumannii. Class Bcarbapenemases, which are metallo-β-lactamases that contain zinc in theactive site, belong to the IMP, VIM, SPM, GIM, and SIM families and havebeen primarily detected in Pseudomonas aeruginosa and have beenincresingly reported in Enterobacteriaceae. Carbapenemases of NMD-1type, OXA-48 and KPC are particularly aimed at by the subject matter ofthe present invention.

An “antibiotic activity” according to the present invention is thegeneric definition as understood by the skilled person, that is to sayan effect of an “antibiotic agent”. Such an “antibiotic agent” is asubstance that kills, blocks or slows the growth of one or morebacteria.

By “growth” is included in the scope of the present invention any celloperation leading to a volumetric increase of the cell (i.e. of thebacterium), a cell division (of the bacteria) or a cell reproduction (ofthe bacteria).

The expression “pharmaceutical composition” in the present inventionmeans any composition comprising an effective dose of a compound of theinvention and at least one pharmaceutically acceptable excipient. Saidexcipients are selected, depending on the pharmaceutical form and thedesired method of administration, from the usual excipients known by aperson skilled in the art.

The expression “pharmaceutically acceptable addition salts” in thepresent invention means all the pharmaceutically acceptable salts of thecompounds according to the invention are included within the scope ofthe invention, in particular the salts of weak acids and of weak bases,for example the hydrochloride salt, hydrobromide salt, trifluoacetatesalt etc.

The terms “drug” or “medicament” are equivalent in the context of thepresent invention.

The expression “treatment” is intended to be directed towards all typesof animals, preferably mammals, more preferably humans. In the case of atreatment of an animal which is not human kind, it will be referred to aveterinary treatment.

DETAILED DESCRIPTION

The subject matter of the present invention concerns a compound aspresently defined characterized in that R₆ represents a chemical moietychosen in the group consisting of C₂-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆alkoxy, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, C₁-C₆ thioalkyl, C₁-C₆ alkylthio,(C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, (C₁-C₆)-haloalkoxy-(C₁-C₆)-alkyl, C₁-C₆haloalkylsulfinyl, C₃-C₆ trialkylsilyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₂-C₆ alkylcarbonyl, C₂-C₆ alkenyloxy, C₂-C₆ alkynyloxy, C₂-C₆alkenylthio, C₂-C₆ alkynylthio, C₂-C₆ haloalkenyl, C₂-C₆ haloalkynyl,C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio, C₂-C₆ haloalkenyloxy,C₂-C₆ haloalkynyloxy, C₂-C₆ haloalkenylthio, C₂-C₆ haloalkynylthio,(C₅-C₁₂)-aryl-(C₁-C₆)-alkyl, mono or polycyclic C₅-C₁₂ aryl or mono orpolycyclic C₃-C₁₂ heteroaryl fragment optionally substituted by one orseveral halogen atoms, nitro, cyano, formyl, C₁-C₆ alkyl, C₃-C₇cycloalkyl, C₁-C₆ alkoxy, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, C₂-C₆alkylcarbonyl, C₁-C₆ alkylthio, C₁-C₆ thioalkyl,(C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₆alkylsulfinyl, C₁-C₆alkylsulfonyl, (C₅-C₁₂)-arylsulfonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,C₁-C₆ haloalkoxy alkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio,C₁-C₆ haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆ trialkylsilyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₂-C₆ haloalkenyl,C₂-C₆ haloalkenyloxy, C₂-C₆ haloalkynyloxy, C₂-C₆ alkenyloxy, C₂-C₆alkynyloxy, C₂-C₆ alkenylthio, C₂-C₆ alkynylthio, C₂-C₆ haloalkenylthio,C₂-C₆ haloalkynylthio and/or nitro fragments, or a monocyclic C₅-C₆ arylgroup optionally substituted by a C₁-C₆ alkyloxy group preferably R₆represents a mono or polycyclic C₅-C₁₂ aryl or heteroaryl fragment(preferably a phenyl fragment), wherein the aryl (phenyl) fragment isoptionally substituted by one or several (notably 1 to 3) halogen atoms,cyano, formyl, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ alkoxy,(C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, C₂-C₆ alkylcarbonyl, C₁-C₆ alkylthio,C₁-C₆ thioalkyl, (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₆alkylsulfinyl,C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkoxyalkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio, C₁-C₆haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆ trialkylsilyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₂-C₆ haloalkenyl, C₂-C₆haloalkenyloxy, C₂-C₆ haloalkynyloxy, C₂-C₆ alkenyloxy, C₂-C₆alkynyloxy, C₂-C₆ alkenylthio, C₂-C₆ alkynylthio, C₂-C₆ haloalkenylthio,C₂-C₆ haloalkynylthio and/or nitro fragments, or a monocyclic C₅-C₆ arylgroup optionally substituted by a C₁-C₆ alkyloxy group, such as a phenylgroup optionally substituted by a C₁-C₆ alkyloxy group, in particular a(4-)methoxyphenyl group. Even more preferably, R₆ represents a mono orpolycyclic C₅-C₁₂ aryl fragment (such as a phenyl group), optionallysubstituted by one or several (notably 1 to 3) halogen atoms, C₁-C₆haloalkyl or C₁-C₆ alkoxy. More preferably, R₆ is a monocyclic arylfragment such as a phenyl group, optionally substituted by one orseveral (notably 1 to 3) halogen atoms, C₁-C₆ haloalkyl or C₁-C₆ alkoxysuch as Cl, I, F, Br, CF₃ or OMe, especially for the method ofpreparation of the compound of formula (I) according to the presentinvention.

The subject matter of the present invention concerns a compound aspresently defined, characterized in that R₁ represents an aryl orheteroaryl fragment, wherein the aryl or heteroaryl fragments areoptionally substituted by

-   -   one or several halogen atoms, hydroxyl (OH), nitro, cyano,        formyl, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, amino-C₁-C₁₀ alkoxy,        (carboxylic acid)-C₁-C₁₀ alkoxy, (carboxylic (C₁-C₆)alkyl        ester)-C₁-C₁₀ alkoxy, (1,2 diol)-C₂-C₁₀ alkoxy,        —O—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-OH, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl,        C₂-C₆ alkylcarbonyl, C₁-C₆ alkylthio, C₁-C₆ thioalkyl,        (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆        alkylsulfonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆        haloalkoxy alkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio,        C₁-C₆ haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆        trialkylsilyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl,        C₂-C₆ haloalkenyl, C₂-C₆ haloalkenyloxy, C₂-C₆ haloalkynyloxy,        C₂-C₆ alkenyloxy, C₂-C₆ alkynyloxy, C₂-C₆ alkenylthio, C₂-C₆        alkynylthio, C₂-C₆ haloalkenylthio, C₂-C₆ haloalkynylthio and/or        a C₁-C₆ alkoxy optionally substituted by a mono or polycyclic        C₅-C₁₂ aryl group, and/or    -   a bridging group of formula —O—CH₂—O— or —O—CH₂CH₂—O—.

In a particular embodiment, R₁ represents an aryl or heteroaryl fragmentoptionally substituted by one or several (notably 1 to 3) C₁-C₆ alkoxy,C₁-C₆ thioalkyl, halogen, amino-C₁-C₁₀ alkoxy, (carboxylic acid)-C₁-C₁₀alkoxy, (1,2 diol)-C₂-C₁₀ alkoxy, (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl esterand/or nitro fragments, especially for the method of preparation of thecompound of formula (I) according to the present invention. Preferably,R₁ is an electro-donating group, especially for the method ofpreparation of the compound of formula (I) according to the presentinvention.

Preferably, the compounds of the present invention are characterized inthat R₁ represents a monocyclic aryl fragment optionally substituted by

-   -   one or several (notably 1 to 3) OH, C₁-C₆ alkyl, C₂-C₆ alkenyl,        C₁-C₆ thioalkyl, halogen, amino-(C₁-C₁₀ alkoxy), (carboxylic        acid)-(C₁-C₁₀ alkoxy), (carboxylic (C₁-C₆)alkyl ester)-C₁-C₁₀        alkoxy, (1,2 diol)-C₂-C₁₀ alkoxy,        —O—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-OH, (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl        ester, nitro and/or a C₁-C₆ alkoxy group optionally substituted        by a mono or polycyclic C5-C12 aryl group, and/or    -   a bridging group of formula —O—CH₂—O— or —O—CH₂CH₂—O—,        especially for the method of preparation of the compound of        formula (I) according to the present invention.

More preferably, the compounds of the present invention arecharacterized in that R₁ represents a monocyclic aryl fragmentoptionally substituted by one or several (notably 1 to 3):

-   -   OH,    -   C₁-C₆ thioalkyl, in particular SCH₃,    -   C₂-C₆ alkenyl, such as —CH═CH₂ (vinyl group),    -   halogen, such as iodine,    -   (carboxylic acid)-(C₁-C₁₀ alkoxy), such as OCH₂COOH,    -   (carboxylic (C₁-C₆)alkyl ester)-C₁-C₁₀ alkoxy, such as        OCH₂COOCH₃, OCH₂COOCH₂CH₃ or OCH₂COOC(CH₃)₃, in particular        OCH₂COOC(CH₃)₃,    -   (1,2 diol)-C₂-C₁₀ alkoxy, such as OCH₂CHOHCH₂OH,    -   —O—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-OH, such as OCH₂CH₂OCH₂CH₂OH,        and/or    -   C₁-C₆ alkoxy group optionally substituted by a mono or        polycyclic C₅-C₁₂ aryl group, such as OCH₃, OCH₂CH₃, OCH₂Ph,        and/or    -   a bridging group of formula —O—CH₂—O— or —O—CH₂CH₂—O—,

even more preferably, R₁ represents a monocyclic aryl fragmentoptionally substituted by

-   -   one or several (notably 1 to 3) OH, C₁-C₆ alkyl, C₁-C₆        thioalkyl, halogen, amino-(C₁-C₁₀ alkoxy), (carboxylic        acid)-(C₁-C₁₀ alkoxy), (carboxylic (C₁-C₆)alkyl ester)-C₁-C₁₀        alkoxy, (1,2 diol)-C₂-C₁₀ alkoxy,        —O—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-OH, (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl        ester, nitro and/or a C₁-C₆ alkoxy group optionally substituted        by a mono or polycyclic C₅-C₁₂ aryl group, and/or    -   a bridging group of formula —O—CH₂—O— or —O—CH₂CH₂—O—,        especially for the method of preparation of the compound of        formula (I) according to the present invention.

More preferably, the compounds of the present invention arecharacterized in that R₁ represents a monocyclic aryl fragmentoptionally substituted by one or several (notably 1 to 3):

-   -   OH,    -   C₁-C₆ thioalkyl, in particular SCH₃    -   halogen, such as iodine,    -   (carboxylic (C₁-C₆)alkyl ester)-C₁-C₁₀ alkoxy, such as        OCH₂COOCH₃, OCH₂COOCH₂CH₃ or OCH₂COOC(CH₃)₃, in particular        OCH₂COOC(CH₃)₃,    -   (1,2 diol)-C₂-C₁₀ alkoxy, such as OCH₂CHOHCH₂OH,    -   —O—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-OH, such as OCH₂CH₂OCH₂CH₂OH,        and/or    -   C₁-C₆ alkoxy group optionally substituted by a mono or        polycyclic C₅-C₁₂ aryl group, such as OCH₃, OCH₂CH₃, OCH₂Ph,        and/or        a bridging group of formula —O—CH₂—O— or —O—CH₂CH₂—O—,        especially for the method of preparation of the compound of        formula (I) according to the present invention.

For instance, the compounds of the present invention are characterizedin that R₁ represents a monocyclic aryl fragment optionally substitutedby one or several C₁-C₆ alkoxy, C₁-C₆ thioalkyl, halogen, amino-(C₁-C₁₀alkoxy), (carboxylic acid)-(C₁-C₁₀ alkoxy), (1,2 diol)-C₂-C₁₀ alkoxy,(C₅-C₁₂)-aryl-(C₁-C₆)-alkyl ester and/or nitro fragments, especially forthe method of preparation of the compound of formula (I) according tothe present invention.

In a particular embodiment, the compounds of the present invention arecharacterized in that R₁ represents a phenyl fragment optionallysubstituted by one or several C₁-C₆ alkoxy, C₁-C₆ thioalkyl, halogen,amino-C₁-C₁₀ alkoxy, (carboxylic acid)-C₁-C₁₀ alkoxy, (2,3diol)-propoxy, (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl ester and/or nitro fragments,especially for the method of preparation of the compound of formula (I)according to the present invention.

In a particular embodiment, the compounds of the present invention arecharacterized in that R₁ represents an aryl fragment substituted by oneor several iodine atoms, methoxy, methylthio, ethyloxy, amino-C₁-C₁₀alkoxy, (carboxylic acid)-C₁-C₁₀ alkoxy, (2,3 diol)-propoxy,(C₅-C₁₂)-aryl-(C₁-C₆)-alkyl ester and/or nitro fragments, especially forthe method of preparation of the compound of formula (I) according tothe present invention.

Yet in a particular embodiment, the compounds of the present inventionare characterized in that R₁ represents an aryl fragment substituted byone or three methoxy groups, one methylthio group, one ethoxy group, oneiodine atom, one (2,3 diol)-propoxy group and/or nitro fragments,especially for the method of preparation of the compound of formula (I)according to the present invention.

In a preferred embodiment, the compounds of the present invention arecharacterized in that R₁ represents a phenyl fragment substituted by oneor three methoxy groups, one methylthio group, one ethoxy group, oneiodine atom, one (2,3 diol)-propoxy group and/or nitro fragments,especially for the method of preparation of the compound of formula (I)according to the present invention.

In a particular embodiment, the compounds of the present invention arecharacterized in that R₁ represents a phenyl fragment, a 4-methoxyphenyl, a 3,4,5-trimethoxyphenyl, a 4-methylthio-phenyl, a4-ethoxy-phenyl, a 4-iodo-phenyl, a 4-nitro phenyl or a 4-[(2,3diol)-propoxy]-phenyl fragments, especially for the method ofpreparation of the compound of formula (I) according to the presentinvention.

In another embodiment, the compounds of the present invention arecharacterized in that R₁ represents a monocyclic aryl fragmentoptionally substituted by one or several halogen atoms, C₁-C₆ alkoxyand/or C₁-C₆ thioalkyl fragments, especially for the method ofpreparation of the compound of formula (I) according to the presentinvention.

Preferably, the compounds of the present invention are characterized inthat R₁ represents a phenyl fragment optionally substituted by one orseveral halogen atoms, C₁-C₆ alkoxy and/or C₁-C₆ thioalkyl fragments,especially for the method of preparation of the compound of formula (I)according to the present invention.

In a particular embodiment, the compounds of the present invention arecharacterized, the compounds of the present invention are characterizedin that R₁ represents an aryl fragment substituted by one or severaliodine atoms, methoxy, methylthio and/or ethyloxy fragments, especiallyfor the method of preparation of the compound of formula (I) accordingto the present invention.

In a particular embodiment, the compounds of the present invention arecharacterized, the compounds of the present invention are characterizedin that R₁ represents an aryl fragment substituted by one iodine atom,one or three methoxy groups, one methylthio group and/or one ethoxygroup, especially for the method of preparation of the compound offormula (I) according to the present invention.

In a preferred embodiment, the compounds of the present invention arecharacterized in that R₁ represents a phenyl fragment substituted by oneiodine atom, one or three methoxy groups, one ethoxy group, onebenzyloxy group, one OCH₂COOH group, one OCH₂COOC(CH₃)₃ group, oneOCH₂CH₂OCH₂CH₂OH group, one OH group, one OCH₂CH₂OCH₂CH₂OH group, onemethylthio group and/or one bridging group of formula —O—CH₂—O— or—O—CH₂CH₂—O—, even more preferably, by one iodine atom, one or threemethoxy groups, one ethoxy group, one benzyloxy group, oneOCH₂COOC(CH₃)₃ group, one OCH₂CH₂OCH₂CH₂OH group, one OH group, oneOCH₂CH₂OCH₂CH₂OH group, one methylthio group and/or one bridging groupof formula —O—CH₂—O— or —O—CH₂CH₂—O—, especially for the method ofpreparation of the compound of formula (I) according to the presentinvention.

In a preferred embodiment, the compounds of the present invention arecharacterized in that R₁ represents a phenyl fragment substituted by oneiodine atom, one or three methoxy groups, one methylthio group and/orone ethoxy group, especially for the method of preparation of thecompound of formula (I) according to the present invention.

In a particularly preferred embodiment, the compounds of the presentinvention are characterized in that R₁ represents a phenyl fragment, a4-hydroxyphenyl, a 4-methoxyphenyl, a 2-methoxyphenyl, a3-methoxyphenyl, a 3,4-dimethoxyphenyl, a 3,4,5-trimethoxyphenyl, a4-methylthio-phenyl, a 4-ethoxy-phenyl, a 4-benzyloxy-phenyl, a1,3-benzodioxole, a 1,4-benzodioxane, a 4-[(2,3 diol)-propoxy]-phenyl, a4-phenoxyacetic acid, a tert-butyl 4-(phenoxy)acetate, a4-(bis(2-hydroxyethyl)ether)phenyl or a 4-iodo-phenyl, even morepreferably, R₁ represents a phenyl fragment, a 4-hydroxyphenyl, a4-methoxy phenyl, a 2-methoxy phenyl, a 3-methoxy phenyl, a3,4-dimethoxyphenyl, a 3,4,5-trimethoxyphenyl, a 4-methylthio-phenyl, a4-ethoxy-phenyl, a 4-benzyloxy-phenyl, a 1,3-benzodioxole, a1,4-benzodioxane, a 4-[(2,3 diol)-propoxy]-phenyl, a tert-butyl4-(phenoxy)acetate, a 4-(bis(2-hydroxyethyl)ether)phenyl or a4-iodo-phenyl, especially for the method of preparation of the compoundof formula (I) according to the present invention.

In another particularly preferred embodiment, the compounds of thepresent invention are characterized in that R₁ represents a phenylfragment, a 4-methoxy phenyl, a 3,4,5-trimethoxyphenyl, a4-methylthio-phenyl, a 4-ethoxy-phenyl or a 4-iodo-phenyl, especiallyfor the method of preparation of the compound of formula (I) accordingto the present invention.

The subject matter of the present invention also concerns a compound asdefined presently, characterized in that R₂ and/or R₃ represent a C₁-C₆haloalkyl, a C₁-C₆ alkoxy, a C₁-C₆ thioalkyl, a C₁-C₆ acyl, nitro and/ora cyano fragments, a mono or polycyclic aryl or heteroaryl fragmentoptionally substituted by one or several halogen atoms, nitro, cyano,formyl, COOH, —COO(C₁-C₆ alkyl), C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆N₃-substituted alkyl, C₁-C₆ NH₂-substituted alkyl, C₁-C₆ alcohol, C₁-C₆alkoxy, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, C₂-C₆ alkylcarbonyl, C₁-C₆alkylthio, C₁-C₆ thioalkyl, (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₆alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,C₁-C₆ haloalkoxy alkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio,C₁-C₆ haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆ trialkylsilyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₂-C₆ haloalkenyl,C₂-C₆ haloalkenyloxy, C₂-C₆ haloalkynyloxy, C₂-C₆ alkenyloxy, C₂-C₆alkynyloxy, C₂-C₆ alkenylthio, C₂-C₆ alkynylthio, C₂-C₆ haloalkenylthio,C₂-C₆ haloalkynylthio, a monocyclic C₅-C₆ aryl group optionallysubstituted by a C₁-C₆ alkyloxy group and/or a COO(C₁-C₆ alkyl) groupwherein the alkyl is substituted by NH₂ or NHCOO(C₁-C₆)alkyl orNHCOO(C₁-C₆)alkyl(mono or polycyclic C₅-C₁₂)aryl (preferably the alkylin the COO(C₁-C₆ alkyl) group is substituted by NHCOO(C₁-C₆)alkyl orNHCOO(C₁-C₆)alkyl(mono or polycyclic C₅-C₁₂)aryl), especially for themethod of preparation of the compound of formula (I) according to thepresent invention.

In particular, R₂ and/or R₃ represent a C₁-C₆ haloalkyl, a C₁-C₆ alkoxy,a C₁-C₆ thioalkyl, a C₁-C₆ acyl, nitro and/or a cyano fragments, a monoor polycyclic aryl or heteroaryl fragment optionally substituted by oneor several halogen atoms, especially for the method of preparation ofthe compound of formula (I) according to the present invention.

Preferably R₂ (and/or R₃) is an electron-enricher group, i.e. anelectron donating group, especially for the method of preparation of thecompound of formula (I) according to the present invention.Specifically, in one embodiment of the present invention, the compoundsof the present invention are characterized in that R₂ and/or R₃represent at least one electron-withdrawing group chosen in the listconsisting of a para-halogenophenyl, a CF₃, a phenyl, a fragmentcomprising a carbonyl such as an acyl, a cyano, a 3-pyridyl, a 4-methoxyphenyl, a 3,4,5-trimethoxyphenyl, a 4-methylthio-phenyl, a4-ethoxy-phenyl, a 4-iodo-phenyl, a 4-nitro phenyl or a 4-[(2,3diol)-propoxy]-phenyl fragment.

Preferably, the compound of the present invention is characterized inthat R₂ and/or R₃ represent a monocyclic aryl, monocyclic heteroaryl orpolycyclic aryl fragment optionally substituted by one or several(notably 1 to 3) halogen atoms, C₁-C₆ NH₂-substituted alkyl, COOH,—COO(C₁-C₆ alkyl), C₁-C₆ N₃-substituted alkyl, C₁-C₆ haloalkyl, C₁-C₆alcohol, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, C₁-C₆ acyl, C₂-C₆ alkenyl,nitro, cyano, a monocyclic C₅-C₆ aryl group optionally substituted by aC₁-C₆ alkyloxy group (such as a phenyl group substituted by a C₁-C₆alkyloxy group, preferably a methoxy group) and/or a COO(C₁-C₆ alkyl)group wherein the alkyl is substituted by NH₂ or NHCOO(C₁-C₆)alkyl orNHCOO(C₁-C₆)alkyl(mono or polycyclic C₅-C₁₂)aryl, fragments (preferablythe alkyl in the COO(C₁-C₆ alkyl) group is substituted byNHCOO(C₁-C₆)alkyl or NHCOO(C₁-C₆)alkyl(mono or polycyclic C₅-C₁₂)aryl),especially for the method of preparation of the compound of formula (I)according to the present invention.

Preferably, the compound of the present invention is characterized inthat R₂ and/or R₃ represent a monocyclic aryl, monocyclic heteroaryl orpolycyclic aryl fragment optionally substituted by one or severalhalogen atoms, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, C₁-C₆ acyl, nitro and/orcyano fragments, especially for the method of preparation of thecompound of formula (I) according to the present invention.

For example, the compound of the present invention is characterized inthat R₂ and/or R₃ represent a phenyl fragment, a pyridyl fragment, or anaphthalene fragment, optionally substituted by one or several (notably1 to 3) halogen atoms, COOH, —COO(C₁-C₆ alkyl), C₁-C₆ N₃-substitutedalkyl, C₁-C₆ NH₂-substituted alkyl, C₁-C₆ haloalkyl, C₁-C₆ alcohol,C₁-C₆ alkoxy, C₁-C₆ thioalkyl, C₂-C₆ alkenyl, C₁-C₆ acyl, nitro, cyano,a monocyclic C₅-C₆ aryl group optionally substituted by a C₁-C₆ alkyloxygroup (such as a phenyl group substituted by a C₁-C₆ alkyloxy group,preferably a methoxy group) and/or a COO(C₁-C₆ alkyl) group wherein thealkyl is substituted by NH₂ or NHCOO(C₁-C₆)alkyl orNHCOO(C₁-C₆)alkyl(mono or polycyclic C₅-C₁₂)aryl, fragments (preferablythe alkyl in the COO(C₁-C₆ alkyl) group is substituted byNHCOO(C₁-C₆)alkyl or NHCOO(C₁-C₆)alkyl(mono or polycyclic C₅-C₁₂)aryl),especially for the method of preparation of the compound of formula (I)according to the present invention.

In particular, the compound of the present invention is characterized inthat R₂ and/or R₃ represent a phenyl fragment, a pyridyl fragment, or anaphthalene fragment, optionally substituted by one or several halogenatoms, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, C₁-C₆ acyl, nitro and/or cyanofragments, especially for the method of preparation of the compound offormula (I) according to the present invention.

More preferably, the compound of the present invention is characterizedin that R₂ and/or R₃ represent an aryl fragment substituted by one orseveral chlorine atoms, fluorine atoms, methoxy, COOH, COOCH₃,COOC(CH₃)₃, COOCH₂CH₂NH₂, COOCH₂CH₂NHCOOC(CH₃)₃, CH₂OH, CH₂N₃, CH₂NH₂,CH₂Cl, vinyl, nitro, 4-methoxyphenyl, and/or cyano fragments, even morepreferably by one or several chlorine atoms, fluorine atoms, methoxy,COOH, COOCH₃, COOC(CH₃)₃, COOCH₂CH₂NHCOOC(CH₃)₃, CH₂N₃, CH₂Cl, nitroand/or cyano fragments, especially for the method of preparation of thecompound of formula (I) according to the present invention.

Even more preferably, the compound of the present invention ischaracterized in that R₂ and/or R₃ represent an aryl fragmentsubstituted by one or several chlorine atoms, fluorine atoms, methoxyfragments, nitro and/or cyano fragments, especially for the method ofpreparation of the compound of formula (I) according to the presentinvention.

Yet more preferably, the compound of the present invention ischaracterized in that R₂ and/or R₃ represent an aryl fragment optionallysubstituted by one, two or three methoxy groups, one methylthio group,one ethoxy group, one iodine atom, one fluorine atom, one or twochlorine atom, one (2,3 diol)-propoxy group, one COOH group, one vinylgroup, one COOCH₃ group, one COOC(CH₃)₃ group, one COOCH₂CH₂NH₂ group,one COOCH₂CH₂NHCOOC(CH₃)₃ group, one CH₂OH group, one CH₂N₃ group, oneCH₂NH₂ group, one CH₂Cl group, one 4-methoxyphenyl, and/or nitrofragments, even more preferably by one, two or three methoxy groups, onemethylthio group, one ethoxy group, one iodine atom, one fluorine atom,one or two chlorine atom, one (2,3 diol)-propoxy group, one COOH group,one COOCH₃ group, one COOC(CH₃)₃ group, one COOCH₂CH₂NHCOOC(CH₃)₃ group,one CH₂N₃ group, one CH₂Cl group, and/or nitro fragments, especially forthe method of preparation of the compound of formula (I) according tothe present invention.

Yet more preferably, the compound of the present invention ischaracterized in that R₂ and/or R₃ represent an aryl fragmentsubstituted by one or three methoxy groups, one methylthio group, oneethoxy group, one iodine atom, one (2,3 diol)-propoxy group and/or nitrofragments, especially for the method of preparation of the compound offormula (I) according to the present invention.

Yet more preferably, the compound of the present invention ischaracterized in that R₂ and/or R₃ represent:

-   -   a phenyl fragment optionally substituted by one methoxy group,        one fluorine atom, one or two chlorine atoms, one vinyl group,        one COOH group, one COOCH₃ group, one COOC(CH₃)₃ group, one        COOCH₂CH₂NH₂ group, one COOCH₂CH₂NHCOOC(CH₃)₃ group, one CH₂OH        group, one CH₂N₃ group, one CH₂NH₂ group, one CH₂Cl group and/or        one 4-methoxyphenyl, preferably a phenyl fragment optionally        substituted by one methoxy group, one fluorine atom, one or two        chlorine atoms, one COOH group, one COOCH₃ group, one COOC(CH₃)₃        group, one COOCH₂CH₂NHCOOC(CH₃)₃ group, one CH₂N₃ group, and/or        one CH₂Cl group,    -   a naphthalene fragment, or    -   a pyridine fragment,        especially for the method of preparation of the compound of        formula (I) according to the present invention.

In a more preferred embodiment, the compound of the present invention ischaracterized in that R₂ and/or R₃ represent an phenyl fragmentsubstituted by one or three methoxy groups, one methylthio group, oneethoxy group, one iodine atom, one (2,3 diol)-propoxy group and/or nitrofragments, especially for the method of preparation of the compound offormula (I) according to the present invention.

In a preferred embodiment, the compound of the present invention ischaracterized in that R₂ and/or R₃ represent a phenyl fragment, a2-naphthalenyl fragment, a 3-pyridyl fragment, a 4-methoxy phenyl, a3,4,5-trimethoxyphenyl, a 4-(hydroxymethyl)-phenyl, a4-methylthio-phenyl, a 4-ethoxy-phenyl, a 4-iodo-phenyl, a4-fluoro-phenyl, a 4-chloro-phenyl, a 3,5-dichloro-phenyl, a 4-nitrophenyl a 4-[(2,3 diol)-propoxy]-phenyl, a 4-(chloromethyl)-phenyl, a4-(azidomethyl)-phenyl, a 4-(aminomethyl)-phenyl, a 4-carboxylicacid-phenyl (i.e a

group), a methyl 4-carboxylate-phenyl (i.e a

group), a tert-butyl 4-carboxylate-phenyl (i.e a

group), a

group (especially as the ammonium salt, such as the correspondingtrifluoroacetate ammonium salt) or a

group, a 4-vinylphenyl group

or a 4-(4-methoxyphenyl)-phenyl group,

preferably a phenyl fragment, a 2-naphthalenyl fragment, a 3-pyridylfragment, a 4-methoxy phenyl, a 3,4,5-trimethoxyphenyl, a4-methylthio-phenyl, a 4-ethoxy-phenyl, a 4-iodo-phenyl, a4-fluoro-phenyl, a 4-chloro-phenyl, a 3,5-dichloro-phenyl, a 4-nitrophenyl a a 4-[(2,3 diol)-propoxy]-phenyl, a 4-(chloromethyl)-phenyl, a4-(azidomethyl)-phenyl, a 4-carboxylic acid-phenyl (i.e a

group), a methyl 4-carboxylate-phenyl (i.e a

group), a tert-butyl 4-carboxylate-phenyl (i.e a

group), or a

group, especially for the method of preparation of the compound offormula (I) according to the present invention.

In a preferred embodiment, the compound of the present invention ischaracterized in that R₂ and/or R₃ represent a phenyl fragment, a3-pyridyl fragment, a 4-methoxy phenyl, a 3,4,5-trimethoxyphenyl, a4-methylthio-phenyl, a 4-ethoxy-phenyl, a 4-iodo-phenyl, a 4-nitrophenyl or a 4-[(2,3 diol)-propoxy]-phenyl, especially for the method ofpreparation of the compound of formula (I) according to the presentinvention.

In another preferred embodiment, the compound of the present inventionis characterized in that R₂ and/or R₃ represent a phenyl fragment, a2-naphthalenyl fragment, a 3-pyridyl fragment, a 4-methoxy phenyl, a3,4,5-trimethoxyphenyl, a 4-(hydroxymethyl)-phenyl, a4-methylthio-phenyl, a 4-ethoxy-phenyl, a 4-iodo-phenyl, a4-fluoro-phenyl, a 4-chloro-phenyl, a 3,5-dichloro-phenyl, a4-(chloromethyl)-phenyl, a 4-(azidomethyl)-phenyl, a4-(aminomethyl)-phenyl, a 4-vinylphenyl group, a4-(4-methoxyphenyl)-phenyl group, a 4-carboxylic acid-phenyl, a methyl4-carboxylate-phenyl, a tert-butyl 4-carboxylate-phenyl a

group (especially as the ammonium salt, such as the correspondingtrifluoroacetate ammonium salt) or a

fragment, preferably a phenyl fragment, a 2-naphthalenyl fragment, a3-pyridyl fragment, a 4-methoxy phenyl, a 3,4,5-trimethoxyphenyl, a4-methylthio-phenyl, a 4-ethoxy-phenyl, a 4-iodo-phenyl, a4-fluoro-phenyl, a 4-chloro-phenyl, a 3,5-dichloro-phenyl, a4-(chloromethyl)-phenyl, a 4-(azidomethyl)-phenyl, a 4-carboxylicacid-phenyl, a methyl 4-carboxylate-phenyl, a tert-butyl4-carboxylate-phenyl or a

fragment, especially for the method of preparation of the compound offormula (I) according to the present invention.

Preferably, R₂ (and/or R₃) is an electron-withdrawing group and R₁ is anelectro-donating group, especially for the method of preparation of thecompound of formula (I) according to the present invention.

In another embodiment, the compound of the present invention ischaracterized in that R₂ and/or R₃ represent monocyclic aryl, monocyclicheteroaryl or polycyclic aryl fragments optionally substituted by one orseveral halogen atoms and/or C₁-C₆ alkoxy fragments, especially for themethod of preparation of the compound of formula (I) according to thepresent invention.

More preferably, the compound of the present invention is characterizedin that R₂ and/or R₃ represent a phenyl fragment optionally substitutedby one or several halogen atoms and/or C₁-C₆ alkoxy fragments,especially for the method of preparation of the compound of formula (I)according to the present invention.

Even more preferably, the compound of the present invention ischaracterized in that R₂ and/or R₃ represent a monocyclic aryl,monocyclic heteroaryl or polycyclic aryl substituted by one or severalchlorine atoms, fluorine atoms and/or methoxy fragments, especially forthe method of preparation of the compound of formula (I) according tothe present invention.

Yet more preferably, the compound of the present invention ischaracterized in that R₂ and/or R₃ represent a phenyl or pyridylfragment optionally substituted by one or several chlorine atoms,fluorine atoms and/or methoxy fragments, especially for the method ofpreparation of the compound of formula (I) according to the presentinvention.

In a more preferred embodiment, the compound of the present invention ischaracterized in that R₂ and/or R₃ represent a phenyl, a 3-pyridyl, a4-methoxy phenyl, a 4-fluoro-phenyl, a 4-chloro phenyl, or a 3,5dichlorophenyl, especially for the method of preparation of the compoundof formula (I) according to the present invention.

Preferably, R₁ is an electro-donating group and R₂ (and/or R₃) is anelectron-withdrawing group, especially for the method of preparation ofthe compound of formula (I) according to the present invention.

The subject matter of the present invention also concerns a compound aspresently defined, characterized in that at least one of R₃, R₄ and R₅represents a hydrogen atom, especially for the method of preparation ofthe compound of formula (I) according to the present invention.

Preferably, the compound of the present invention is characterized inthat at least two of R₃, R₄ and R₅ represent a hydrogen atom, especiallyfor the method of preparation of the compound of formula (I) accordingto the present invention.

Preferably, the compound of the present invention is characterized inthat R₃, R₄ and R₅ represent hydrogen atoms, especially for the methodof preparation of the compound of formula (I) according to the presentinvention. In this embodiment, R₂ preferably represents a monocyclicaryl, monocyclic heteroaryl or polycyclic aryl fragment optionallysubstituted by one or several (notably 1 to 3) halogen atoms, COOH,—COO(C₁-C₆ alkyl), C₁-C₆ N₃-substituted alkyl, C₁-C₆ haloalkyl, C₁-C₆alcohol, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, C₁-C₆ acyl, nitro, cyano and/ora COO(C₁-C₆ alkyl) group wherein the alkyl is substituted by NH₂ orNHCOO(C₁-C₆)alkyl or NHCOO(C₁-C₆)alkyl(mono or polycyclic C₅-C₁₂)aryl,fragments, especially for the method of preparation of the compound offormula (I) according to the present invention. In particular, R₂represents:

-   -   a phenyl fragment optionally substituted by one methoxy group,        one fluorine atom, one or two chlorine atoms, one COOH group,        one COOCH₃ group, one COOC(CH₃)₃ group, one COOCH₂CH₂NH₂ group,        one COOCH₂CH₂NHCOOC(CH₃)₃ group, one CH₂OH group, one CH₂N₃        group, and/or one CH₂Cl group, preferably a phenyl fragment        optionally substituted by one methoxy group, one fluorine atom,        one or two chlorine atoms, one COOH group, one COOCH₃ group, one        COOC(CH₃)₃ group, one COOCH₂CH₂NHCOOC(CH₃)₃ group, one CH₂N₃        group, and/or one CH₂Cl group,    -   a naphthalene fragment, or    -   a pyridine fragment.

In this embodiment, R₆ represents a mono or polycyclic C₅-C₁₂ arylfragment, optionally substituted by one or several (notably 1 to 3)halogen atoms, C₁-C₆ haloalkyl or C₁-C₆ alkoxy, more preferably, R₆ is amonocyclic aryl fragment such as a phenyl group, optionally substitutedby one or several (notably 1 to 3) halogen atoms, C₁-C₆ haloalkyl orC₁-C₆ alkoxy such as Cl, I, F, Br, CF₃ or OMe. Even more preferably, inthis specific embodiment, the compounds of the present invention arepreferably characterized in that R₁ represents a monocyclic arylfragment optionally substituted by

-   -   one or several (notably 1 to 3) OH, C₁-C₆ alkyl, C₁-C₆        thioalkyl, halogen, amino-(C₁-C₁₀ alkoxy), (carboxylic        acid)-(C₁-C₁₀ alkoxy), (carboxylic (C₁-C₆)alkyl ester)-C₁-C₁₀        alkoxy, (1,2 diol)-C₂-C₁₀ alkoxy,        —O—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-OH, (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl        ester, nitro and/or a C₁-C₆ alkoxy group optionally substituted        by a mono or polycyclic C₅-C₁₂ aryl group, and/or    -   a bridging group of formula —O—CH₂—O— or —O—CH₂CH₂—O—.

The subject matter of the present invention moreover concerns a compoundas presently defined, especially for the method of preparation of thecompound of formula (I) according to the present invention,characterized in that:

-   -   R₁ represents a fragment chosen from the group consisting of        phenyl, 4-methoxy phenyl, 4-ethoxy-phenyl, 4-nitro phenyl,        3,4,5-trimethoxyphenyl, 4-methylthio-phenyl, 4-iodo-phenyl; and    -   R₂ and/or R₃ represent a fragment chosen from the group        consisting of phenyl, 4-methoxy phenyl, 4-formylphenyl, 4-nitro        phenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl,        naphtyl, indolyl, furanyl, pyridyl, thiophenyl.

The subject matter of the present invention preferably concerns acompound as presently defined, especially for the method of preparationof the compound of formula (I) according to the present invention,characterized in that:

-   -   R₁ represents a fragment chosen from the group consisting of        phenyl, 4-methoxy phenyl, a 3,4,5-trimethoxyphenyl,        4-methylthio-phenyl, 4-ethoxy-phenyl or 4-iodo-phenyl    -   R₂ and/or R₃ represent a fragment chosen from the group        consisting of phenyl, 4-methoxy phenyl, 4-formylphenyl, 4-nitro        phenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl,        naphtyl, indolyl, furanyl, pyridyl, thiophenyl.

It is understood that the present invention concerns any combination ofparticular and/or preferred embodiments of R₁, R₂, R₃, R₄, R₅ and R₆.

In a particular embodiment, especially for the method of preparation ofthe compound of formula (I) according to the present invention, thesubject matter of the present invention concerns the molecules of thefollowing structure:

salts or solvates thereof.

More specifically, especially for the method of preparation of thecompound of formula (I) according to the present invention, the subjectmatter of the present invention concerns the molecules of the followingstructure:

salts or solvates thereof.

In particular, especially for the method of preparation of the compoundof formula (I) according to the present invention, the subject matter ofthe present invention concerns the molecules of the following structure:

salts or solvates thereof.

The subject matter of the present invention thus also concerns a methodto prepare a compound of formula (I) as defined above, including theexplicitly excluded compounds above, implicating a compound of formula(II):

wherein R₄, R₆ and R₇ are as defined above.

Preferably, R₄ and R₆ have the same definitions in formula (II) as inthe case of formula (I) with, if need be, protecting groups on thereacting functions thereof.

R₇ preferably is an electron-withdrawing group such as chosen in thegroup consisting of carbamates, a sulphonamide, amides and sulfonyles.

More preferably, R₇ is chosen in the group consisting of Boc (i.e.tert-butyloxycarbonyl), acetamide, mesylate or tosylate.

In a particular embodiment of the present invention, R₆—N—R₇ forms atleast one ring, comprising e.g. lactames, oxazolidinone, or evensultames. More specifically, R₆—N—R₇ forms 2 or even 3 rings wherein atleast one of the rings is a hydrocarbon ring, which can be saturated,unsaturated or aromatic.

The compound(s) of the present invention can be produced, and used inthe form of mixtures of enantiomers and/or diasteroisomers.

The expression “mixtures of enantiomers” in the present invention meansany mixture of enantiomers. The mixtures can be racemic, i.e. 50/50% ofeach enantiomer in weight (w/w), or non-racemic, i.e. enriched in one orthe other of the enantiomer so that the ratios w/w are between 50/50%and 75/25%, between 75/25% and 90/10% or above 95% of one enantiomer incomparison with the other.

The expression “mixtures of diastereoisomers” in the present inventionmeans any mixture of diastereoisomers in any proportions.

Moreover, the subject matter of the present invention concerns at leastone compound of formula (I) for its use as an antibiotic or for its usein combination with an antibiotic characterized in that the antibioticis effective on bacteria chosen from gram-negative bacteria such asEnterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii,preferably drug resistant forms of gram-negative bacteria to one orseveral classes of antibiotics comprising β-lactams by production of aβ-lactamase.

In a particular embodiment, the present invention concerns a compositionof several compounds of formula (I), in particular for its use as a drug(antibiotic), in the form of a mixture of enantiomers and/ordiasteroisomers of formula (I).

In another particular embodiment, the present invention concerns acomposition of several compounds of formula (I), in particular for itsuse in combination with at least one known antibiotic as definedhereunder, in the form of a mixture of enantiomers and/ordiasteroisomers of formula (I).

The subject matter of the present invention thus also concerns acompound of formula (I) (in its different variants) for its use as apotentiating agent, preferably of an antibiotic.

Indeed, the combination of at least one compound of formula (I) with atleast one antibiotic advantageously provides a potentiating effect, i.e.by “potentiating effect/action” it is meant according to the presentinvention that at least one of the active compounds acts either as a“suicide molecule” as explained above enabling the other activeingredient to be active (i.e. antibiotic), and/or increases the activityof at least one of the other compounds present in term of biological(i.e. antibiotic) activity through e.g. a synergistic effect.

Therefore, said compounds of formula (I) according to the presentinvention can be used alone, or in combination with each other, or atleast one other antibiotic already known. The derivatives thereof, ifthey have antibiotic activity, can also be used.

Examples of known antibiotics already used as medicaments specific inthis field which can be used in combination with at least one compoundof the present invention, and whose effect may be potentiated by thecompound(s) of formula (I) of the present invention, can belong to atleast one of the families consisting of the beta-lactam family (such asan amoxicillin and/or ampicillin), the cephalosporin family (such ascephazolin), the tetracycline family (such as chlortetracycline), therifamycin family (such as rifampicin), the peptide family (such as apolymyxin), the aminoside family (such as streptomycin), the phenicolfamily (such as chloramphenicol), the macrolide family (such aserythromycin).

Preferably, the combination comprises at least one known beta-lactamantibiotic. Examples of beta lactams preferentially used according tothe present invention comprise carbapenems such as imipenem, meropenem,ertapenem and the compound commonly known as “PZ-601”.

In yet another embodiment, the known antibiotic(s) is/are selected fromthe group consisting of the amoxicillin, ampicillin, carbapenems,cephazolin the cephalosporins, the glycopeptides, the polymyxins, thegramicidins, tyrocidin, the aminosides, the macrolides, thelincosamides, the synergistins, the phenicols, the tetracyclines,fusidic acid, the oxazolidinones, the rifamycins, the quinolones, thefluoroquinolones, the sulfamides, trimethoprim, and the mixturesthereof.

More preferably, the known antibiotic is selected from the groupconsisting of the penicillins, oxacillin, cloxacillin, ampicillin,meropenem, ertapenem, PZ-601, amoxicillin, bacampicillin, metampicillin,pivampicillin, azlocillin, mezlocillin, piperacillin, ticarcillin,pivmecillinam, sulbactam, tazobactam, imipenem, cephalexin, cephydroxii,cephaclor, cephatrizine, cephalotin, cephapirin, cephazolin, cephoxitin,cephamandole, cephotetan, cephuroxime, cephotaxime, cephsulodin,cefepime, cephoperazone, cephotiam, cephtazidime, cephtriaxone,cephixime, cephpodoxime, cephepime, colistin, latamoxef, aztreonam,vancomycin, vancocin, teicoplanin, polymyxin B, colistin, bacitracin,tyrothricin, streptomycin, kanamycin, tobramycin, amikacin, sisomycin,dibekacin, netilmycin, spectinomycin, spiramycin, ceftazidime,erythromycin, josamycin, roxithromycin, clarithromycin, azithromycin,lincomycin, clindamycin, virginiamycin, pristinamycin,dalfopristine-quinupristine, chloramphenicol, thiamphenicol,tetracycline, doxycycline, minocycline, fusidic acid, linezolide,rifamycin, rifampicin, nalidixic acid, oxolinic acid, pipemidic acid,flumequin, pefloxacin, norfloxacin, ofloxacin, ciprofloxacin, enoxacin,sparfloxacin, levofloxacin, moxifloxacin, nitroxolin, tilboquinol,nitrofurantoin, nifuroxazide, metronidazole, ornidazole, sulfadiazine,sulfamethisol, trimethoprim, isoniazide and the derivatives and mixturesthereof. Said antibiotics, and more particularly amoxicillin, canoptionally be used in association with yet at least one anotherantibiotic activity enhancer such as clavulanic acid.

The present invention thus also relates to a pharmaceutical compositioncomprising at least one compound of formula (I) as presently disclosedand to the (medical) use(s) of said composition, advantageously as anantibiotic. Preferably the pharmaceutical composition of the presentinvention comprises only two therapeutically active substances, at leastone of which is a compound of formula (I) as presently disclosed.

In particular embodiment of the present invention, the pharmaceuticalcomposition comprises at least two compounds of formula (I) as presentlydisclosed.

Moreover, the second therapeutically active substance comprised in thepharmaceutical composition of the invention can be an antibiotic whichis already known as such and already used as medicament specific in thisfield and whose activity is potentiated.

Preferably, the pharmaceutical composition of the present inventioncomprises at least two therapeutically active substances, one of whichexerts a potentiating action on the other(s).

Examples of known antibiotics already used as medicaments specific inthis field (such as those cited above) can be used in the pharmaceuticalcomposition of the invention, said known antibiotics' effect may bepotentiated by the first therapeutically active substance (i.e. compoundof formula (I) according to the present invention, including theexcluded compound thereof), as explained above.

Of course, the pharmaceutical composition according to the invention isnot restricted to the use of only those antibiotics mentioned above. Infact, considering the potentiating effect exerted by the compounddefined in the invention of formula (I), other known or futureantibiotics can also be successfully used.

These pharmaceutical compositions can be administered orally, rectally,parenterally, intramuscularly or locally by topical application on theskin and the mucosa. In all cases, the pharmaceutical form of thepharmaceutical composition of the invention shall be adapted to its use.For example, it can be used in the form of a solution, suspension,tablet . . . for oral administration. The compositions for parenteraladministration are generally pharmaceutically acceptable sterilesolutions or suspensions which can optionally be prepared immediatelybefore use. The aqueous solutions may be suitable for intravenousadministration in so far as the pH is properly adjusted and they aremade isotonic, for example by adding a sufficient amount of sodiumchloride or glucose.

The compositions according to the present invention can be solid orliquid and present in pharmaceutical forms in current use in humanmedicine or veterinary use such as, for example, simple or coatedtablets, capsules, granules, suppositories, injectable preparations,ointments, creams, gels; they are prepared according to the usualmethods.

The active principle or principles can be incorporated in the excipientsusually used in these pharmaceutical compositions, such as cellulosederivatives (HPMC, HPC, microcrystalline cellulose, etc.), talc, gumArabic, lactose, starch, magnesium stearate, cocoa butter, aqueous orother media, fatty bodies of animal or plant origin, paraffinderivatives, glycols, different wetting, dispersing or emulsifyingagents, preservatives. These compositions can notably take the form of alyophilisate designed to be dissolved as required in an appropriatesolvent, for example pyrogen free sterile water.

The compound(s) and/or pharmaceutical composition(s) according to theinvention can be formulated so as to be suitable for a simultaneous orsequential administration of said at least one compound of formula (I)according to the invention and known antibiotic agent(s) as definedabove.

The pharmaceutical composition of the invention thus enables thetreatment of local or systemic infections caused by resistantmicroorganisms using doses of the compound of formula (I) the presentinvention, or combinations thereof eventually with known antibioticagent(s) as defined above.

In the case of such a combination, the active substance are preferablylower than the doses required for treating the same infections due tosusceptible microorganisms with one or the other of these same saidcompound of formula (I) according to the invention and known antibioticagent as defined above alone.

The result is to offer a treatment which has at least the followingadvantages:

-   -   effectiveness at very low doses against nonresistant        microorganisms,    -   effectiveness against microorganisms resistant to at least one        therapeutic agent,    -   control of recurrence phenomena, and/or    -   control of phenomena of resistant microorganisms selection.

Advantageously, there is a notable reduction in the risks of toxicityand/or adverse effects (well known to the person of the art for theknown antibiotics), thanks to the potentiation which enables theadministration of very low doses.

The pharmaceutical compositions of the invention are a simple andefficient means to combat the problems related to microbial agents ingeneral which comprise mainly resistance to therapeutic agents andtoxicity of the latter resulting from the use of high doses.

A method according to the present invention for treating patients havinga bacterial infection consists in administering to said patients thedose, determined by the physician, of the pharmaceutical composition ofthe invention comprising suitable doses of at least one compound offormula (I) according to the invention, combined with suitable doses ofat least one said known antibiotic agent(s) as defined above.

In a particular embodiment of the present invention, the compositionsthus include at least two active principles, one of which at least is acompound of formula (I) as defined presently, which can be administeredsimultaneously, separately or spread over time. They can for example beprovided in kit form, allowing the administration of a compound ofgeneral formula (I) and that of another antibacterial compoundseparately.

The present invention also proposes a kit characterized in that itcomprises at least one first container containing a firsttherapeutically active compound of formula (I) (including all variants,such as the excluded compounds above) and mixtures thereof, and at leastone second container containing a second therapeutically activesubstance which is an antibiotic, in particular as defined above. Thekit of the invention preferably contains instructions for use. Said kitenables health care personnel to prepare on demand either a mixture ofsuitable doses of the desired first therapeutic substance(s) and of thedesired antibiotic(s), for a simultaneous administration, or tosequentially and separately administer the suitable dose of at least onesaid first therapeutically active substance, followed by the suitabledose of at least one said second therapeutically active substance, thatis, the suitable antibiotic, or vice versa. However, a mixture forsimultaneous use shall be preferred for ease of administration.

Therefore the present invention in particular concerns a kit comprising:

-   -   at least one first container containing a first therapeutically        active compound of formula (I) as defined in any one of claims 1        to 6 or as defined in claim 7 and mixtures thereof, and    -   at least one second container containing a second        therapeutically active substance which is an antibiotic, as a        combination product for simultaneous, sequential and separate        use, in particular in antibiotherapy.

The dose administered of the compounds of formula (I) can vary dependingon the severity and nature of the condition being treated, theparticular subject, the administration route and the other antibacterialproduct involved. It can be, for example, between 0.1 mg and 1 g per kgper day, by oral route in humans or for veterinary purposes, or between0.05 mg and 0.5 g per kg per day by intramuscular or intravenous routein humans or for veterinary purposes. The dose of the knownantibacterial compound can also vary depending on the condition beingtreated, the particular subject, the administration route and theproduct involved, but generally follows the typical doses prescribed bypractitioners, for example for human administration as described in theFrench reference Vidal. This dose can range up to 10 g per day perpatient, or even more. Nevertheless, as a result of the potentiationprovided by the compounds of general formula (I) to the knownantibacterial compound(s), doses of the latter as part of thecombination can be reduced compared to standard doses. The inventivecombinations can also be used as disinfectants for surgical instruments.

Another subject matter of the present invention concerns the method toprepare a compound of formula (I) of the present invention whichcomprises in a first step (a) the addition of a compound of formula (II)as defined above with a compound of formula (III),

wherein fragments R₁, R₂, R₃ have the same definitions as in the case offormula (I) with, if need be, protecting groups on the reactingfunctions thereof.

In a preferred embodiment, at least one of the fragments of R₂ or R₃ informula (III) is an electron-withdrawing group.

Preferably “electron-withdrawing group”, in the context of the presentinvention, especially for the method of preparation of the compound offormula (I) according to the present invention, means that none of R₂ orR₃ in formula (III) is a mesomeric attracting fragment.

In another preferred embodiment, especially for the method ofpreparation of the compound of formula (I) according to the presentinvention, the fragment R₁ in formula (III) is an electro-donating group(equivalent to “electro-enriching group”).

R₁ may be for example p-methoxyphenyl. The article “Tetrahedron Lett.2006 47, 8109” shows how to cut off the p-methoxyphenyl moiety and thusliberate the secondary amine, which in turn can be substituted byanother R₁. This can of course be applicable to other types of R₁.

In a more preferred embodiment, the fragment R₁ in formula (II) is anelectro-donating group, and at least one of the fragments of R₂ or R₃ informula (II) is an electron-withdrawing group, especially for the methodof preparation of the compound of formula (I) according to the presentinvention. Therefore, in yet a more preferred embodiment, at least oneof the fragments of R₂ or R₃ in formula (II) is an inductive attractingfragment such as a para-halogenophenyl, and the fragment R₁ in formula(II) is an electro-donating group, whilst none of R₂ or R₃ in formula(III) is a mesomeric attracting fragment, especially for the method ofpreparation of the compound of formula (I) according to the presentinvention.

Preferably compound of formula (II) is added to compound of formula(III) with an excess of compound of formula (II). The excess of compound(II) is preferably superior to 1.5 equivalents (i.e. in moles) ofcompound (III). More preferably, the excess of compound (II) iscomprised between 2 equivalents and 10 equivalents of compound (III).

The addition of step (a) is completed in the presence of a base B1.

Preferably, B1 is a tert-butanolate salt, such as t-BuONa, t-BuOLi,t-BuOK or t-BuONa. Preferably B1 is t-BuOLi.

In yet another embodiment, step (a) comprises an excess of base B1proportionally to compound (II) in relation to compound (III). Theexcesses of compound (II) and B1 are preferably superior to 1.5equivalents (i.e. in moles) of compound (III) (i.e. 1.5 equivalents ofcompound (II) and 1.5 equivalent of B1 in respect to compound (III)).More preferably, the excesses of compound (II) and B1 are comprisedbetween 2 equivalents and 10 equivalents of compound (III).

The addition of step (a) may also be conducted in the presence of apolar solvent, such as dimethylformamide (“DMF”), preferably with acontent of water inferior to 5% molar, more preferably with a content ofwater inferior to 1% molar (i.e. “dry”), yet in a more preferableembodiment without substantially any water (i.e. “extra dry”). In themost preferred embodiment, step (a) comprises dry or extra dry DMF.

Furthermore the addition of step (a) may be conducted under microwaves,preferably for a period of time comprised between 1 minute and 24 hours,more preferably between 5 minutes and 5 hours, even more preferablybetween 10 minutes and 1 hour, such as around (±5 minutes) 20 minutes,30 minutes, 40 minutes or 50 minutes.

In a preferred embodiment, step (a) also comprises silicagel, preferablybetween 0.5 and 5 equivalents in reference to the imine of formula(III). More preferably, step (a) comprises silicagel between 0.8 and 2equivalents in referenced to the imine (III). In yet a more preferredembodiment, step (a) comprises around (±0.1 equivalent) 1 equivalent ofsilicagel.

Moreover, the reaction of step (a) can be made under pressure and/or ata temperature above 50° C.

Preferably the pressure is greater than 1.5 bar, more preferably greaterthan 2 bars, even more preferably greater than 3 bars.

The temperature of the reaction of step (a) is preferably greater than60° C., more preferably greater than 75° C., even more preferablygreater than 85° C. In a particular preferred embodiment of the presentinvention, the temperature of step (a) is fixed at around 100° C., i.e.100° C.±5° C.

Moreover, the method of preparation of the compound of formula (I) asdefined above can be characterized in that the reaction of step (a) ismade without the presence of a metal compound, such as copper, whetherit is in its metallic or one of its oxidized or reduced forms.

In a particular embodiment of the present invention, the method toprepare a compound of formula (I) of the present invention thuscomprises in its first step (a), the addition of a compound of formula(II) with a compound of formula (III) as defined above, in the presenceof a base B1 which can be a tert-butanolate salt or an equivalent basethereof, such as phenolates, methanolates or hydroxides, wherein saidaddition of the compounds is made in a polar solvent such as dry orextra dry DMF.

In a preferred embodiment of the present invention, the method toprepare a compound of formula (I) of the present invention comprises inits first step (a) the addition of a compound of formula (II) with acompound of formula (III) as defined above, in the presence of a base B1which can be a tert-butanolate salt or an equivalent base thereof, saidaddition of the compounds is made in dry or extra dry DMF wherein thereaction of step (a) is made under pressure and/or at a temperatureabove 50° C., preferably greater than 75° C., such as 85° C.±5° C. or100° C.±5° C.

In yet a preferred embodiment of the present invention, the method toprepare a compound of formula (I) of the present invention comprises ina first step (a) the addition of a compound of formula (II) with acompound of formula (III) as defined above, in the presence of a base B1which is a tert-butanolate salt or an equivalent base thereof, saidaddition of the compounds is made in dry or extra dry DMF, and whereinthe reaction of step (a) is made under microwaves and under pressureand/or at a temperature above 50° C., preferably greater than 75° C.,such as 85° C.±5° C. or 100° C.±5° C.

In an even more preferred embodiment of the present invention, themethod to prepare a compound of formula (I) of the present inventioncomprises in its first step (a) the addition of a compound of formula(II), wherein at least one of R₂ or R₃ is an electron-withdrawing group,with a compound of formula (III) as defined above, in the presence of abase B1 which is a tert-butanolate salt or an equivalent base thereof,said addition of the compounds is made in dry or extra dry DMF, andwherein the reaction of step (a) is made under microwaves and underpressure and/or at a temperature above 50° C., preferably greater than75° C., such as 85° C.±5° C. or 100° C.±5° C.

In an even more preferred embodiment of the present invention, themethod to prepare a compound of formula (I) of the present inventioncomprises in its first step (a) the addition of a compound of formula(II), wherein R₁ is an electro-donating group, with a compound offormula (III) as defined above, in the presence of a base B1 which is atert-butanolate salt or an equivalent base thereof, said addition of thecompounds is made in dry or extra dry DMF, and wherein the reaction ofstep (a) is made under microwaves and under pressure and/or at atemperature above 50° C., preferably greater than 75° C., such as 85°C.±5° C. or 100° C.±5° C.

In an even more preferred embodiment of the present invention, themethod to prepare a compound of formula (I) of the present inventioncomprises in its first step (a) the addition of a compound of formula(II), wherein R₁ is an electro-donating group and at least one of R₂ orR₃ is an electron-withdrawing group, with a compound of formula (III) asdefined above, in the presence of a base B1 which is a tert-butanolatesalt or an equivalent base thereof, said addition of the compounds ismade in dry or extra dry DMF, and wherein the reaction of step (a) ismade under microwaves and under pressure and/or at a temperature above50° C., preferably greater than 75° C., such as 85° C.±5° C. or 100°C.±5° C.

It is another subject matter of the present invention to propose severalimines of formula (III). The obtaining of imines is well documented inthe art. Two methods have been used to obtain these compounds. These twomethods (“Condition A” and “Condition B”) both use the substitution ofthe oxygen atom of a carbonyl by the nitrogen atom of an amine:

R₁, R₂, R₃ are as defined above, with adequate protecting groups ifneed-be.

The conditions A comprise silica (1 equivalent) in ethanol as solvent.Preferably ultra sounds are used at ambient temperature (20-25° C.). Thetime left for the reaction to proceed can for example be comprisedbetween 1 min and 10 hours, preferably around one hour (±20 minutes).

The conditions B comprise toluene as solvent at reflux, for exampleusing a Dean-Stark apparatus. Water appears as a sub product due to thecondensation, and thus may be trapped by any convenient means, ifneed-be. The time left for the reaction to proceed can for example becomprised between 1 hour and 2 days, preferably around one day (±1hour).

The method of preparation of the compound of formula (I) according tothe present invention can furthermore comprise an optional step (b) ofaddition of R₅ as defined above in the case of formula (I), R₅ beingconveniently protected if need-be, through a nucleophilic addition tothe compound obtained in step (a).

Preferably the nucleophilic addition can be conducted with R₅—X, whereinX is a halogen atom in the presence of a base B2. Preferably B2 is anon-nucleophilic base, such as N,N-diisopropylethylamine (“DIPEA”),1,8-diazabicycloundec-7-ene (“DBU”), triethylamine,2,6-di-tert-butylpyridine, phosphazene bases such as t-Bu-P₄, lithiumdiisopropylamide (“LDA”), silicon based amides such as sodium orpotassium bis(trimethylsilyl)amide (“NaHMDS” and “KHMDS”),1-Lithio-2,2,6,6-tetramethylpiperidine (“LiTMP” also called “harpoonbase”), sodium hydride, potassium hydride, or even sodium butoxide,potassium butoxide or lithium butoxide.

The method of preparation of the compound of formula (I) according tothe present invention finally comprises a step (c) of retrieving thecompound of formula (I) as defined presently.

By “retrieving” it is understood according to the present invention thatthe products obtained are extracted by techniques common in the art,e.g. by means of a two-phase washing comprising for example an organicsolvent and water; alternatively, it is possible to recover the productsin suspension (either in the form of crystals or amorphous solids) inthe liquid that contains them, by filtration or drainage. Another way torecover the products may simply evaporate or freeze dry the solvent thatcontains them. This recovery phase may further contain a purificationstep by washing the obtained solid or to pass the compounds on achromatography column.

EXAMPLES

The invention shall become clearer in the following examples describingdifferent embodiments, which are given for purposes of illustration andnot by way of limitation.

Example 1: Reaction Conditions Establishment

Different operating conditions involving imines, ynamides and at least abase were tested in order to prepare azetidinimine feature (Table 1).

TABLE 1 Reaction conditions establishment Entry # Base Solvent T (° C.)Heating Time Adjuvant Observations TBAF dry 60-80 ▭ 48 h — imine + 1MTHF DMF ynamide, no 13 t-BuONa dry AT — 24 h Yb(OTf)₃ imine + ynamide +DMF 60-80 ▭ 48 h — reduced imine No evolution 14 TBAF dry AT — 24 hYb(OTf)₃ imine + ynamide + 1M THF DMF 60-80 ▭ 48 h — reduced imine Noevolution 15 DBU dry AT — 24 h — imine + ynamide + DMF 60-80 ▭ 48 h —imine reduite No evolution

Different conditions of reaction were produced using bases, solvents,adjuvants at different reaction temperatures and times. In theconditions set in this first study (i.e. particular chemical structuresof imine and ynamide), the type of base “tert-butoxide” seemed requiredas well as the use of extra dry DMF (sold in a bottle with septumcontaining a sieve in the DMF) (entry 11). The method of preparing acompound of formula (I) according to the present invention thus ispreferably conducted with a step (a) comprising less than 5% mol ofwater, relative to the solvent, more preferably less than 3% mol, orless than 1% mol of water, relative to the solvent. In the mostpreferred embodiment of the method of the invention, no water is presentin step (a) of said method. The method of preparing a compound offormula (I) according to the present invention thus is preferablyconducted with a step (a) comprising a base B1 which is a tert-butoxide.

Example 2: Optimization of the Reaction Conditions

After having verified the possibility to access the desired compound,the previously determined method was optimized by studying the bestreaction conditions (Table 2)

TABLE 2 optimization of the method Entry # Base Solvent T (° C.) HeatingTime Adjuvant Observations 11 t- dry DMF AT — 24 h — imine + ynamide +BuONa azetidinimide 1 t- dry DMF 60 ▭ 16 h — No evolution BuONa 2 t- dryDMF 25 MW 10 min — imine + azetidinimide BuONa (ratio crude NMR 97/3:imine/azet.) 80 MW 30 min — imine + azetidinimide (ratio crude NMR90/10: imine/azet.) 80 MW  1 h — imine + azetidinimide (ratio crude NMR80/20: imine/azet.) 3 t- THF 57 MW  1 h — imine + ynamide BuONa(distilled) 4 t-BuOK dry DMF 80 MW  1 h — imine + azetidinimide (ratiocrude NMR 48/52: imine/azet.) 46% isolated 5 t-BuOK dry DMF 80 MW  1 hNo imine + azetidinimide (ratio molecular crude NMR 45/55: sieve*imine/azet.) 6 t-BuOLi dry DMF 80 MW  1 h — imine + azetidinimide (ratiocrude NMR 50/50: imine/azet.) 7 t-BuOK dry DMF 80 MW  1 h 2 eq. ofimine + azetidinimide (ratio ynamide crude NMR 37/63: imine/azet.) 45%isolated 8 t-BuOK Toluene 100 MW  1 h — imine - no more ynamide - noazetidinimine 9 t-BuOK dry DMF 80 ▭  1 h Slow MS - no reaction additionof ynamide at 80° C. 16 h MS - no reaction - no evolution 10 t-BuOK dryDMF AT ▭ 1 h-4 d — MS - no reaction 11 t-BuOK dry DMF 80 MW  1 h 2 eq.of No improvement base 12 t-BuOLi dry DMF 80 MW  1 h No No improvementmolecular sieve - 2 eq. of base 13 t-BuOLi dry DMF 80 MW  1 h With Noimprovement - seems molecular cleaner sieve - 2 eq. of base 14 t-BuOLidry DMF 80 MW  1 h With No improvement - seems molecular more dirtysieve - 10 eq. of base 15 t-BuOLi N- 80 MW  1 h — MS - no reactionmethylacetamide 16 t-BuOLi ACN 65 MW  1 h — MS - no reaction 17 t-BuOLidry DMF 80 ▭  1 h Round MS - no reaction bottom flask + refrigerant 16 hNo improvement 48 h No improvement 18 t-BuOLi dry DMF 80 ▭  1 h sealedTraces of azetidinimine tube 16 h No improvement 48 h No improvement 19t-BuOLi dry DMF 80 MW 2 h — No improvement  1 h 1 equiv. No improvementof ynamide added 20 t-BuOLi dry DMF 80 MW  1 h 10 mol % MS - no reactionof t-BuOLi 21 t-BuOLi dry DMF 80 MW  1 h More Traces of azetidinimineconcentrated - 0.16M vs. 0.33M 22 t-BuOLi dry DMF 80 MW  1 h less MS -no reaction concentrated - 0.66M vs. 0.33M 23 t-BuOLi dry DMF 80 MW  1 hSmaller No improvement tube MW 100  1 h — conversion improved 24 t-BuOLidry DMF 120 MW  1 h smaller Degradation product tube MW 150  1 h No moredegradation product 25 t-BuOLi dry DMF 100 MW  1 h silicagel Clearimprovement added 2.5 eq. 26 t-BuOLi dry DMF 100 MW  1 h silicagelFormation of a secondary added 2.5 supplementary product eq. + 2 eq. ofbase 27 t-BuOLi dry DMF 100 MW  1 h silicagel Same as entry 4-1.0 eq.added 1.0 seems to be enough eq. 28 t-BuOLi dry DMF 100 MW  1 hsilicagel Formation of a secondary added supplementary product 10.0 eq.29 t-BuOLi dry DMF 100 MW  1 h Alumina Same as entry 4 added 1.0 eq. 30t-BuOLi dry DMF 100 MW  1 h Addition No improvement of 10 mol % 31t-BuOLi dry DMF 100 MW  1 h 3 eq. of Conversion of the imine ynamideclearly improved but the reaction is more dirty 32 t-BuOLi dry DMF 100MW  1 h 3 eq. of No improvement, on the ynamide 3 contrary times with 20min interspace *3A molecular sieve being present in other cases in orderto avoid parasite reactions with water. (wherein MW = microwave)

This study showed that the use of lithium tert-butoxide was particularlyfavorable to the reaction conditions previously set. The method ofpreparing a compound of formula (I) according to the present inventionthus is preferably conducted with a step (a) comprising a base B1 whichis lithium tert-butoxide. Furthermore, the reaction time could bereduced to 1 hour by use of microwaves to an optimized temperature of100° C. The method of preparing a compound of formula (I) according tothe present invention thus is preferably conducted with a step (a)comprising microwaves for a period of time stretching up e.g. up to 24hours, preferably around 1 hour (±15 minutes), at a temperature above80° C., preferably around 100° C. (±10° C.). It was therefore determinedthat the use of e.g. microwaves makes it possible to obtain in asignificant quantity the desired product.

Other parameters were also studied. The most relevant parameter was theaddition of silicagel which proved to be particularly favorable to thereaction. Indeed, the use of 1 equivalent of Silicagel was sufficient tosignificantly increase the conversion of the starting imine. The methodof preparing a compound of formula (I) according to the presentinvention thus is preferably conducted with a step (a) comprisingsilicagel, preferably in a quantity of around 1 equivalent (±0.1 eq) inrespect of the product at the lowest quantity engaged in the reaction,e.g. the imine. Finally it was also found that the conversion of theimine could be improved with the use of an excess of ynamide (2 equiv.)accompanied by a proportional base B1 excess (2 equiv.). The method ofpreparing a compound of formula (I) according to the present inventionthus is preferably conducted with a step (a) comprising an excess ofynamide, e.g. around 2 eq. (±0.1 eq.) in respect of the imine. Themethod of preparing a compound of formula (I) according to the presentinvention thus is preferably conducted with a step (a) comprising anexcess of base B1, e.g. around 2 eq. (±0.1 eq.) in respect of the imine.More preferably, the method of preparing a compound of formula (I)according to the present invention thus is conducted with a step (a)comprising an excess of ynamide, e.g. around 2 eq. (±0.1 eq.) in respectof the imine, accompanied by a proportional base B1 excess, e.g. around2 eq. (±0.1 eq.) in respect of the imine.

Multiple optimization tests were summarized in Table 2. The conditionsadopted for the rest of the study were as follows: ynamide (2 eq.);imine (1 eq.); t-BuOLi (2 eq.); Silicagel (1 eq.); extra dry DMF; 100°C., 1 h, micro-waves. The method of preparing a compound of formula (I)according to the present invention thus is preferably conducted with astep (a) comprising around 2 equivalents of ynamide, around 1 equivalentof imine, around 2 equivalents of t-BuOLi, around 1 equivalent ofsilicagel in extra dry DMF at around 100° C., for 1 h, undermicro-waves.

Example 3: Variation of the Imine

An aromatic imine family was first prepared using mainly two methods(Table 3).

TABLE 3 imine syntheses Entry R₂ R₁ method R(%) 1 C₆H₅ 4-(OMe)C₆H₄ 1 862 4-(OMe)C₆H₄ C₆H₅ 1 82 3 4-(NO₂)C₆H₄ 4-(OMe)C₆H₄ 1 86 4 4-(OMe)C₆H₄4-(OMe)C₆H₄ 1 88 5 4-(F)C₆H₄ 4-(OMe)C₆H₄ 1 94 6 4-(CN)C₆H₄ 4-(OMe)C₆H₄ 167 7 C₆H₅ 3,4,5-(OMe)₃C₆H₂ 1 72 8 C₆H₅ 4-(NO₂)C₆H₄ 2 57 9 4-(Cl)C₆H₄4-(OMe)C₆H₄ 1 80 10 2-(F)C₆H₄ 4-(OMe)C₆H₄ 1 10 11 2,4-(Cl)₂C₆H₃4-(OMe)C₆H₄ 1 89 12

4-(OMe)C₆H₄ 1 0 13

4-(OMe)C₆H₄ 1 0 14

4-(OMe)C₆H₄ 1 0 15

4-(OMe)C₆H₄ 1 12 16

4-(OMe)C₆H₄ 1 0 17

4-(OMe)C₆H₄ 2 equivalents 1 98

These imines were then engaged in the conditions to produceazetidinimine starting from ynamide as previously established (Table 4).

TABLE 4 Preparation of azetidinimines by imine variation Entry # R₂ R₁R(%) 1 C₆H₅ 4-(OMe)C₆H₄ 55 2 4-(OMe)C₆H₄ C₆H₅ 46 3 4-(NO₂)C₆H₄4-(OMe)C₆H₄ 0 4 4-(OMe)C₆H₄ 4-(OMe)C₆H₄ 40 5 4-(F)C₆H₄ 4-(OMe)C₆H₄ 83 64-(CN)C₆H₄ 4-(OMe)C₆H₄ 0 7 C₆H₅ 3,4,5-(OMe)₃C₆H₂ 54 8 C₆H₅ 4-(NO₂)C₆H₄ 09 4-(Cl)C₆H₄ 4-(OMe)C₆H₄ 86 10 2-(F)C₆H₄ 4-(OMe)C₆H₄ 0 11 2,4-(Cl)₂C₆H₃4-(OMe)C₆H₄ 53 12

4-(OMe)C₆H₄ — 13

4-(OMe)C₆H₄ — 14

4-(OMe)C₆H₄ — 15

4-(OMe)C₆H₄ 24 16

4-(OMe)C₆H₄ — 17

4-(OMe)C₆H₄ —

The application of the method was verified, i.e. the desired compoundswere generally obtained in good yields. As previously mentioned, thestudy showed that the reaction was promoted when the imine wassubstituted by an electro donating group R₁ and/or anelectron-withdrawing group in position R2 (and/or R3 according toformula (I) of the present invention).

Moreover, the p-methoxyphenyl group is a particular good choice for R₁,because of its electron donor character and various procedures describedin literature (see e.g. Tetrahedron Lett. 2006 47, 8109) show how to cutoff the p-methoxyphenyl moiety and thus liberate the secondary amine.

Moreover, the use of para-halophenyl as R₂ fragment proved particularlyeffective with excellent yields of up to 86%. The attractor inductivecharacter of these derivatives could be the cause of such success.However, when electron-withdrawing mesomeric derivatives were used as R₂fragments, it was rarely possible to observe the desired product insignificant quantities.

Example 4: Biological Tests

These tests were conducted by comparing UV absorbance slope measurementsof impenem alone, and then imipenem with the concerned azetidinimines atgiven concentrations in the presence of the enzyme. It was thus possibleto monitor the hydrolysis of imipenem. Lower the value of the slope, thehigher is the percentage of inhibition of the enzyme.

Stability tests of imipenem with increasing concentrations of testedmolecules of the present invention (T4#1, i.e. compound #1 of table 4;T4#7 i.e. compound #7 of table 4; T4#9 i.e. compound #9 of table 4; T4#2i.e. compound #2 of table 4) were also conducted (Table 2).

TABLE 5 Stability tests Slope Slope Slope Slope Entry C (μM) T4#1 T4#7T4#9 T4#2 1 100 506 174 390 321 2 10 50 10 38 30 3 1 9 0 2 3Moreover, the different biology test results made on the compounds ofthe present invention are summarized in the table 6.

TABLE 6 Biology tests results summary NDM-1 Enzyme OXA-48 Enzyme KPCEnzyme C Inhibition IC₅₀ C Inhibition IC₅₀ C Inhibition IC₅₀ Structures(μM) % (μM) (μM) % (μM) (μM) % (μM)

10 90 2-5 No reported effect ND ND  ≈7 Enantiomer 1 10 97  <5 ND ND ND10 70  <10 C₂₂H₂₀N₂O MW: 318.1576 Enantiomer 2 10 95  <5 ND ND ND 10 45 >10 C₂₂H₂₀N₂O MW: 318.1576

50 78  >50 No reported effect ND ND  >50

10 96 2-5 50 21 Solubility problems 50 44  ≈20

20 58  >10 No reported effect No reported effect

10 67 5-10 10 3 ND 10 7 ND

10 9 ND No reported effect 10 10 ND

5 97 2.5-5 5 15 ND 5 84 2.5-5

5 94 2.5-5 20 94 10-20 10 99   5-7

100 23 >100 No reported effect 100 12 >100

5 98  <1 10 15 ND 20 82  <10

5 100 0.5-5 10 45 >10 5 100  <5

N.D. N.D.    0.7 N.D. N.D.    7.5 N.D. N.D.    2.7

N.D. N.D.    1.1. N.D. N.D.    9.2 N.D. N.D.    3.3

N.D. N.D.    0.5 N.D. N.D. >50 N.D. N.D.    2.9

10 100 N.D. N.D. N.D. >50 N.D. N.D.    2

10 100 N.D. N.D. N.D. >50 N.D. N.D.    3.6

N.D. N.D.    0.6 N.D. N.D.    7.4 N.D. N.D.    2.4

N.D. N.D.    0.5 N.D. N.D.    6.2 N.D. N.D.    2.5

N.D. N.D.    0.5 N.D. N.D.    8.5 N.D. N.D.    2.9

N.D. N.D.    0.4 10 31 N.D. 10 86 N.D.

N.D. N.D. 5-10 10 9 N.D. 10 17 N.D.

N.D. N.D.    5 10 20 N.D. 10 6 N.D

N.D. N.D.    1.3 N.D. N.D. >50 N.D. N.D.   5-10

N.D. N.D.    1.3 N.D N.D. >50 N.D. N.D.   5-10

N.D. N.D.    0.4 N.D. N.D. >50 N.D. N.D. 2.5-5

N.D. N.D.    1.1. N.D. N.D. >50 N.D. N.D.   5-10

N.D. N.D.    4.8 10 3.5 N.D. 10 6 N.D.

N.D. N.D.    1.2 No measurable effect at 10 μM N.D. N.D.    6

N.D. N.D.    1.8 10 32 N.D. 10 45 N.D.

N.D. N.D.    2.6 N.D N.D >50 N.D. N.D.    1.3

N.D. N.D.    0.7 N.D. N.D. >50 N.D. N.D.  >50

N.D. N.D.    0.6 N.D. N.D >50 N.D. N.D.  >50

N.D. N.D.    0.8 N.D. N.D. >10 N.D. N.D.  >50

N.D. N.D.    3.6 N.D. N.D. >10 N.D. N.D.   5-7

N.D. N.D.    2.9 N.D. N.D. >50 N.D. N.D.    10

N.D. N.D.    2.5 No measurable effect at 10 μM N.D. N.D.    6

10 100 N.D. N.D. N.D. >50 10 89 N.D.

Example 5: Experimental Section 1. General Remarks

Melting points were measured in capillary tubes on a Büchi B-540apparatus and are uncorrected. Infrared spectra were recorded on aPerkin Elmer Spectrum BX FT-IR spectrometer. Proton (1H) and carbon(13C) NMR spectra were recorded on Bruker spectrometers: Avance 300 MHz(QNP—13C, 31P, 19F—probe or Dual 13C probe) and Avance 500 MHz (BB0—ATMprobe or BBI—ATM probe). Carbon NMR (13C) spectra were recorded at 125or 75 MHz, using a broadband decoupled mode with the multiplicitiesobtained using a JMOD or DEPT sequence. NMR experiments were carried outin deuterochloroform (CDCl3), chemical shifts (δ) are reported in partsper million (ppm) with reference to CDCl3 (1H: 7.26; 13C: 77.00). Thefollowing abbreviations are used for the proton spectra multiplicities:s: singlet, bs: broad singlet, d: doublet, t: triplet, q: quartet, m:multiplet, br: broad. Coupling constants (J) are reported in Hertz (Hz).Mass spectra were obtained either with a LCT (Micromass) instrumentusing electrospray ionization (ES), or from a Time of Flight analyzer(ESI-MS) for the high resolution mass spectra (HRMS). Elemental analyseswere performed on a Perkin Elmer CHN 2400 analyzer with detection bycatharometry. Thin-layer chromatography was performed on silica gel 60F254 on aluminium plates (Merck) and visualized under a UVP MineralightUVLS-28 lamp (254 nm) and with ninhydrin and phosphomolybdic acid inethanol. Flash chromatography was conducted on Merck silica gel 60(40-63 μm) at medium pressure (300 mbar) or on CombiFlash apparatus(Serlabo Technologies), using standard settings. Chiral High PressureLiquid Chromatography (HPLC) was performed on a Waters 2695 SeparationsModule equipped with a diode array UV detector (254 nm) and with aDaicel CHIRACEL IA column (4.6*250 nm, 5 mm). Data are reported asfollows: column temperature, eluent, flow rate, retention time.Microwaves irradiation experiments were carried out in an Anton PaarMonowave 300 instrument with internal optic-fiber- or IR temperaturecontrol.

All reagents were obtained from commercial suppliers unless otherwisestated. Where necessary, organic solvents were routinely dried and/ordistilled prior to use and stored over molecular sieves under nitrogencommercial DMF (anhydrous DMF was purchased from Sigma-Aldrich inSure/Seak™ Bottles. Organic extracts were dried over magnesium sulfate(MgSO₄).

2. General Procedures General Procedure A: Imine Formation

Aldehyde (1.0 equiv.), aniline (1.0 equiv.) and silica (1.0 equiv.) aresuccessively added in a round bottom flask followed by the addition ofethanol (0.7M). The mixture is then placed in an ultrasound unit for5-10 minutes (monitored by TLC) and filtered to remove silica. Afterconcentration under reduced pressure, the crude imine is recrystallizedin absolute ethanol.

General Procedure B: Azetidinimine Formation

Imine (1.0 equiv.), ynamide (2.0 equiv.), t-BuOLi (2.0 equiv.) andsilica (1.0 equiv.) are successively added in a microwave sealed tubeplaced under argon before the addition of extra dry DMF (0.3M). Thesealed tube is caped and placed in a microwave apparatus for 1 h at 100°C. After cooling, the crude material is transferred in a round bottomflask, concentrated under reduced pressure and purified by flashchromatography or preparative TLC on silica gel with appropriatedsolvents.

General Procedure C: Formation of Carboxylic Acids from Tert-ButylEsters Under Acidic Hydrolysis Conditions

A solution of the corresponding tert-butyl ester in DCM (1 mL/30 mg oftert-nutyl ester) is cooled to 0° C. then TFA (trifluoroacetic acid, 1mL, excess) is added. After 1 h (thin layer chromatography (TLC)monitoring), the mixture is cooled to 0° C. then a saturated aqueoussolution of NaHCO₃ is added dropwise until pH 7. The aqueous layer isextracted once with DCM (dichloromethane). The organic layers are washedwith water and brine, dried over sodium sulfate, filtered thenevaporated under reduced pressure. The resulting residue is purified byautomated flash chromatography using a gradient of MeOH in DCM (MeOH0%→40% over 20 min).

General Procedure D: Demethylation or the t-Butyl Ester Hydrolysis withBBr₃

An argon-flushed and stirred solution of azetidinimine in anhydrousdichloromethane (DCM) (at a concentration of around 0.1 M) is cooled at−78° C., then BBr₃ (1M solution in DCM, 4 equiv.) is added dropwise. Thesolution is further stirred at −78° C. for 2 h then allowed to warm toroom temperature. Once the reaction completed (TLC monitoring), thereaction mixture is carefully quenched at −78° C. with a 1:1 mixture ofMeOH/DCM (10 mL). After warming to room temperature, the solvents areevaporated then the crude residue is resolubilized in DCM, washed withsaturated aqueous NaHCO₃ and water. The organic layer is dried on sodiumsulfate, filtered then evaporated under reduced pressure. The resultingresidue is subsequently purified by automated flash chromatography usinga gradient of AcOEt in heptane (AcOEt 0%→60% over 30 min).

3. Analytical Data for some Azetidinimines Products According to thePresent Invention

E)-N-(1-(4-methoxyphenyl)-4-phenylazetidin-2-ylidene)aniline

C₂₂H₂₀N₂O—Exact Mass: 328,1576; ¹H NMR (300 MHz, CDCl₃): (ppm) 7.37-7.16(m, 9H), 6.99-6.92 (m, 3H), 6.72 (d, J=9.1 Hz, 2H), 5.07 (dd, J=6.1, 2.9Hz, 1H), 3.66 (s, 3H), 3.42 (dd, J=14.6, 6.1 Hz), 2.86 (dd, J=14.6, 2.9Hz). ¹³C NMR (75 MHz, CDCl₃): (ppm) 154.8 (C), 154.1 (C), 148.6 (C),139.4 (C), 133.7 (C), 129.1 (2CH), 128.9 (2CH), 128.3 (CH), 125.9 (2CH),122.8 (CH), 122.2 (2CH), 117.5 (2CH), 114.2 (2CH), 58.2 (CH), 55.5(CH₃), 40.5 (CH₂). HRMS (ESI): calc. for C₂₂H₂₁N₂O [M+H] m/z 328.1576,found m/z 329.1658. IR (neat): 2993, 2931, 2894, 1668, 1592, 1510, 1486,1390, 1256, 1241, 1162, 1035 cm⁻¹.

(E)-N-(4-phenyl-1-(3,4,5-trimethoxyphenyl)azetidin-2-ylidene)aniline

C₂₄H₂₄N₂O₃—Exact Mass: 388,1787; ¹H NMR (300 MHz, CDCl₃): (ppm)7.51-7.26 (m, 7H), 7.12-7.01 (m, 3H), 6.78 (s, 2H), 5.16 (dd, J=6.0, 2.9Hz, 1H), 3.79 (s, 3H), 3.73 (s, 6H), 3.54 (dd, J=14.8, 6.0 Hz, 1H), 3.00(dd, J=14.8, 2.9 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃): (ppm) 153.4 (2C),148.0 (C), 136.2 (C), 132.8 (C), 129.1 (2CH), 129.0 (2CH), 128.5 (CH),127.6 (C), 126.0 (2CH), 123.0 (CH), 122.2 (C), 122.1 (CH), 94.2 (2CH),92.6 (C), 60.9 (CH), 58.6 (CH₃), 56.0 (2CH₃), 40.4 (CH₂). HRMS (ESI):calc. for C₂₄H₂₅N₂O₃ [M+H] m/z 389.1787, found m/z 389.1871

(E)-N-(4-(4-chlorophenyl)-1-(4-methoxyphenyl)azetidin-2-ylidene)aniline

C₂₂H₁₉ClNO₂—Exact Mass: 362,1186; ¹H NMR (300 MHz, CDCl₃): (ppm)7.34-7.25 (m, 6H), 7.24-7.16 (m, 2H), 6.73 (d, J=9.1 Hz, 2H), 5.04 (dd,J=6.0, 2.8 Hz, 1H), 3.67 (s, 3H), 3.42 (dd, J=14.6, 6.0 Hz, 1H), 2.81(dd, J=14.6, 2.8 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃): (ppm) 155.0 (C),153.6 (C), 148.4 (C), 138.0 (C), 134.1 (C), 133.4 (C), 129.3 (2CH),129.0 (2CH), 127.3 (2CH), 123.0 (CH), 122.2 (2CH), 117.5 (2CH), 114.3(2CH), 57.5 (CH), 55.5 (CH₃), 40.5 (CH₂). HRMS (ESI): calc. for C₂₂H₂₀³⁵ClNO₂ [M+H] m/z 363.1186, found m/z 363.1246; calc. for C₂₂H₂₀ ³⁷ClNO₂[M+H] m/z 365.1156, found m/z 365.1251

(E)-N-(4-(4-methoxyphenyl)-1-phenylazetidin-2-ylidene)aniline

C₂₂H₂₀N₂O—Exact Mass: 328,1576; ¹H NMR (300 MHz, CDCl₃): (ppm) 7.38 (d,J=8.3 Hz, 2H), 7.32-7.11 (m, 6H), 7.01-6.93 (m, 3H), 6.92-6.80 (m, 3H),5.06 (dd, J=6.0, 2.8 Hz, 1H), 3.73 (s, 3H), 3.41 (dd, J=14.8, 6.0 Hz,1H), 2.84 (dd, J=14.8, 2.8 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃): (ppm) 159.6(C), 154.5 (C), 149.3 (C), 139.9 (C), 131.3 (C), 128.9 (2CH), 128.8(2CH), 127.2 (2CH), 123.0 (CH), 122.2 (2CH), 122.1 (CH), 116.4 (2CH),114.5 (2CH), 57.8 (CH), 55.3 (CH₃), 40.5 (CH₂). HRMS (ESI): calc. forC₂₂H₂₁N₂O [M+H] m/z 329.1576, found m/z 329.1638.

(E)-N-(1,4-bis(4-methoxyphenyl)azetidin-2-ylidene)aniline

C₂₃H₂₂N₂O₂—Exact Mass: 358,1681; ¹H NMR (300 MHz, CDCl₃): (ppm)7.42-7.25 (m, 6H), 7.05-6.96 (m, 3H), 6.88 (d, J=8.6 Hz, 2H), 6.78 (d,J=8.9 Hz, 2H), 5.08 (dd, J=5.6, 3.0 Hz, 1H), 3.78 (s, 3H), 3.72 (s, 3H),3.45 (dd, J=14.7, 5.6 Hz, 1H), 2.90 (dd, J=14.7, 3.0 Hz, 1H). ¹³C NMR(75 MHz, CDCl₃): (ppm) 159.3 (C), 154.5 (C), 148.1 (C), 133.2 (C), 131.0(C), 129.1 (CH), 127.4 (CH), 126.9 (C), 123.0 (CH), 122.5 (CH), 117.8(CH), 114.7 (CH), 114.4 (CH), 58.1 (CH), 55.7 (CH₃), 55.5 (CH₃), 40.8(CH₂). HRMS (ESI): calc. for C₂₃H₂₃N₂O₂ [M+H] m/z 359.1681, found m/z359.1752.

(E)-4-(4-chlorophenyl)-N-(4-iodophenyl)-1-(4-methoxyphenyl)azetidin-2-imine

¹H NMR (300 MHz, CDCl₃): δ 7.57 (d, J=8.4 Hz, 2H), 7.36-7.33 (m, 6H),6.82 (d, J=9.3 Hz, 2H), 6.78 (d, J=8.7 Hz, 2H), 5.14 (dd, J=6.0, 3.0 Hz,1H), 3.76 (s, 3H), 3.49 (dd, J=14.7, 6.0 Hz, 1H), 2.87 (dd, J=14.7, 3.0Hz, 1H). HRMS: [M+H]⁺ m/z 489.0230, found 489.0240.

(E)-N-(4-iodophenyl)-1-(4-methoxyphenyl)azetidin-2-imine

¹H NMR (300 MHz, CDCl₃): δ 7.58 (d, J=8.4 Hz, 2H), 7.41-7.36 (m, 7H),6.81 (d, J=4.5 Hz, 2H), 6.79 (d, J=4.2 Hz, 2H), 5.15 (dd, J=5.6, 3.0 Hz,1H), 3.75 (s, 3H), 3.48 (dd, J=14.7, 6.0 Hz, 1H), 2.93 (dd, J=14.7, 3.0Hz, 1H). HRMS: [M+H]⁺ m/z 455.0542, found 455.0624.

(E)-4-(4-chlorophenyl)-N-(4-chlorophenyl)-1-(4-methoxyphenyl)azetidin-2-imine

¹H NMR (300 MHz, CDCl₃): δ 7.37-7.23 (m, 8H), 6.94 (d, J=8.7 Hz, 2H),6.81 (d, J=9.0 Hz, 2H), 5.15 (dd, J=6.0, 3.0 Hz, 1H), 3.76 (s, 3H), 3.50(dd, J=14.7, 6.0 Hz, 1H), 2.89 (dd, J=14.7, 6.0 Hz, 1H). HRMS: [M+H]⁺m/z 398.0874, found 398.0898.

(E)-4-N-(4-chlorophenyl)-1-(4-methoxyphenyl)azetidin-2-imine

¹H NMR (300 MHz, CDCl₃): δ 7.41-7.23 (m, 9H), 6.97 (d, J=8.4 Hz, 2H),6.82 (d, J=8.7 Hz, 2H), 5.16 (dd, J=5.9, 2.7 Hz, 1H), 3.75 (s, 3H), 3.49(dd, J=14.7, 5.9 Hz, 1H), 2.92 (dd, J=14.7, 2.7 Hz, 1H). HRMS: [M+H]⁺m/z 363.1264, found 363.1268.

(E)-4-(4-chlorophenyl)-N-(4-trifluoromethylphenyl)-1-(4-methoxyphenyl)azetidin-2-imine

¹H NMR (300 MHz, CDCl₃): δ 7.42-7.27 (m, 8H), 7.18 (d, J=7.8 Hz, 2H),6.82 (d, J=9.0 Hz, 2H), 5.17 (dd, J=6.0, 2.7 Hz, 1H), 3.77 (s, 3H), 3.53(dd, J=14.7, 6.0 Hz, 1H), 2.91 (dd, J=14.7, 2.7 Hz, 1H). HRMS: [M+H]⁺m/z 431.1138, found 431.1131.

(E)-1-(4-ethoxyphenyl)-N-(4-methoxyphenyl)-4-(naphthalen-2-yl)azetidin-2-imine

¹H NMR (300 MHz, CDCl₃): δ 7.89-7.83 (m, 2H), 7.56-7.43 (m, 7H), 7.02(d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 6.79 (d, J=9.0 Hz, 2H), 5.30(dd, J=6.0, 3.0 Hz, 1H), 3.95 (q, J=13.8, 6.9 Hz, 2H), 3.80 (s, 3H),3.57 (dd, J=14.7, 6.0 Hz, 1H), 2.99 (dd, J=14.7, 3.0 Hz, 1H), 1.37 (t,J=13.8, 6.9 Hz, 2H). HRMS: [M+H]⁺ m/z 423.1993, found 423.1987.

(E)-1-(4-ethoxyphenyl)-N-(4-iodophenyl)-4-(naphthalen-2-yl)azetidin-2-imine

¹H NMR (300 MHz, CDCl₃): δ 7.89-7.40 (m, 7H), 6.82 (d, J=8.4 Hz, 2H),6.79 (d, J=9.0 Hz, 2H), 5.32 (dd, J=5.7, 2.7 Hz, 1H), 3.95 (q, J=5.7,2.7 Hz, 2H), 3.54 (dd, J=14.4, 6.0 Hz, 1H), 2.99 (dd, J=14.4, 2.7 Hz,1H), 1.36 (t, J=6.0, 2.7 Hz, 2H). HRMS: [M+H]⁺ m/z 519.0944, found519.0941.

(E)-4-(3,5-dichlorophenyl)-N-(4-iodophenyl)-1-(4-methoxyphenyl)azetidin-2-imine

¹H NMR (300 MHz, CDCl₃): δ 7.56 (d, J=8.7 Hz, 2H), 7.45 (d, J=1.8 Hz,2H), 7.37-7.21 (m, 3H), 6.86 (d, J=9.3 Hz, 2H), 6.75 (d, J=8.4 Hz, 2H),5.49 (dd, J=6.3, 3.0 Hz, 1H), 3.78 (s, 3H), 3.60 (dd, J=14.7, 6.3 Hz,1H), 2.93 (dd, J=14.7, 3.0 Hz, 1H). HRMS: [M+H]⁺ m/z 538.9968, found538.9920.

(E)-1-(4-(benzyloxy)phenyl)-N-4-diphenylazetidin-2-imine

¹H NMR (300 MHz, CDCl₃): δ 7.49-7.20 (m, 14H), 7.11-6.98 (m, 3H),6.93-6.81 (m, 2H), 5.15 (dd, J=6.0, 2.9 Hz, 1H), 5.00 (s, 2H), 3.5 (dd,J=14.6, 6.0 Hz, 1H), 2.94 (dd, J=14.6, 2.9 Hz, 1H). HRMS-EI (m/z) calcdfor C₂₈H₂₅N₂O [(M+H)⁺] 405.1967, found 405.1952.

(E)-1-(3,4-dimethoxyphenyl)-N-4-diphenylazetidin-2-imine

¹H NMR (300 MHz, CDCl₃): δ 7.52 (d, J=2.3 Hz, 1H), 7.48-7.22 (m, 7H),7.06-6.99 (m, 3H), 6.72 (d, J=8.6 Hz, 1H), 6.64 (dd, J=8.6, 2.3 Hz, 1H),5.15 (dd, J=6.1, 2.9 Hz, 1H), 3.8 (2 overlaps s, 6H), 3.52 (dd, J=14.6,6.1 Hz, 1H), 2.97 (dd, J=14.7, 2.9 Hz, 1H). HRMS-EI (m/z) calcd forC₂₃H₂₃N₂O₂ [(M+H)⁺] 359.1760, found 359.1763.

(E)-1-(benzo[d][1,3]dioxol-5-yl)-N,4-diphenylazetidin-2-imine

¹H NMR (300 MHz, CDCl₃): δ 7.46-7.22 (m, 8H), 7.12-6.97 (m, 3H), 6.77(dd, J=8.4, 2.1 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 5.88 (dd, J=2.7, 1.4Hz, 2H), 5.12 (dd, J=6.1, 2.9 Hz, 1H), 3.50 (dd, J=14.7, 6.1 Hz, 1H),2.93 (dd, J=14.7, 2.9 Hz, 1H). HRMS-EI (m/z) calcd for C₂₂H₁₉N₂O₂[(M+H)⁺] 343.1448, found 343.1453.

(E)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-4-diphenylazetidin-2-imine

¹H NMR (300 MHz, CDCl₃): δ 7.49-7.22 (m, 7H), 7.08-6.98 (m, 4H), 6.95(dd, J=8.7, 2.5, 1H), 6.74 (d, J=8.7 Hz, 1H), 5.11 (dd, J=6.1, 2.9 Hz,1H), 4.27-4.13 (m, 4H), 3.48 (dd, J=14.7, 6.1 Hz, 1H), 2.92 (dd, J=14.7,2.9 Hz, 1H). HRMS-EI (m/z) calcd for C₂₃H₂₁N₂O₂ [(M+H)⁺] 357.103, found357.1588.

(E)-1-(3-methoxyphenyl)-N,4-diphenylazetidin-2-imine

¹H NMR (300 MHz, CDCl₃): δ 7.45-7.21 (m, 8H), 7.14 (t, J=8.1 Hz, 1H),7.09-7.00 (m, 3H), 6.96-6.89 (m, 1H), 6.53 (ddd, J=8.1, 2.5, 0.8 Hz,1H), 5.17 (dd, J=6.2, 3.0 Hz, 1H), 3.75 (s, 3H), 3.51 (dd, J=14.8, 6.2Hz, 1H), 2.95 (dd, J=14.8, 3.0 Hz, 1H). HRMS-EI (m/z) calcd forC₂₂H₂₀N₂O [(M+H)⁺] 329.1654, found 329.1658.

(E)-4-(4-chlorophenyl)-1-(3-methoxyphenyl)-N-phenylazetidin-2-imine

¹H NMR (300 MHz, CDCl₃): δ 7.38-7.23 (m, 6H), 7.23-6.97 (m, 5H), 6.88(dd, J=8.0, 1.0 Hz, 1H), 6.54 (ddd, J=8.0, 2.5, 1.0 Hz, 1H), 5.14 (dd,J=6.2, 3.0 Hz, 1H), 3.76 (s, 3H), 3.52 (dd, J=14.8, 6.2 Hz, 1H), 2.90(dd, J=14.8, 3.0 Hz, 1H). HRMS-EI (m/z) calcd for C₂₂H₂₀ClN₂O [(M+H)⁺]363.1264, found 363.1250.

(E)-4-(4-chlorophenyl)-1-(2-methoxyphenyl)-N-phenylazetidin-2-imine

¹H NMR (300 MHz, CDCl₃): δ 8.31-8.23 (m, 1H), 7.28-7.14 (m, 6H),7.00-6.86 (m, 5H), 6.69-6.64 (m, 1H), 5.52 (dd, J=6.0, 2.8 Hz, 1H), 3.48(s, 3H), 3.44 (dd, J=14.7, 6.0 Hz, 1H), 2.80 (dd, J=14.7, 2.8 Hz, 1H).HRMS-EI (m/z) calcd for C₂₂H₂₀ClN₂O [(M+H)⁺] 363.1264, found 363.1273.

Methyl (E)-4-(1-phenyl-4-(phenylimino)azetidin-2-yl)benzoate

¹H NMR (300 MHz, CDCl₃): δ 8.06 (d, J=8.7 Hz, 2H), 7.5 (d, J=8.7 Hz,2H), 7.42 (d, J=8.7 Hz, 2H), 7.33-7.22 (m, 4H), 7.08-6.95 (m, 4H), 5.24(dd, J=6.3 Hz, 3.0 Hz, 1H), 3.92 (s, 3H), 3.55 (dd, J=14.8, 6.3 Hz, 1H),2.93 (dd, J=14.8, 3.0 Hz, 1H). HRMS-ESI (m/z) calcd for C₂₃H₂₁N₂O₂[(M+H)⁺] 357.1603, found 357.1589.

(E)-N-(1,4-diphenylazetidin-2-ylidene)aniline

¹H NMR (300 MHz, CDCl₃): δ 7.48-7.23 (m, 12H), 7.08-6.95 (m, 3H), 5.19(dd, J=6.4, 2.8 Hz, 1H), 3.52 (dd, J=14.8, 6.4 Hz, 1H), 2.96 (dd,J=14.8, 2.8 Hz, 1H). HRMS-ESI (m/z) calcd for C₂₁H₁₉N₂ [(M+H)⁺]299.1548, found: 299.1563.

(E)-tert-butyl4-(1-(4-methoxyphenyl)-4-(phenylimino)azetidin-2-yl)benzoate (MBG132MBG135)

¹H NMR (300 MHz, CDCl₃): δ 8.03 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz,2H), 7.40-7.29 (m, 5H), 7.06 (m, 3H), 6.82 (d, J=8.0 Hz, 1H), 5.21 (dd,J=15.0, 6.0 Hz, 1H), 3.77 (s, 3H), 3.55 (dd, J=15.0, 6.0 Hz, 1H), 2.94(dd, J=15.0, 3.0, 1H), 1.61 (s, 9H). HRMS-ESI (m/z) calcd for C₂₇H₂₉N₂O₃[(M+H)⁺] 429.2178, found: 429.2187.

tert-butyl (E)-4-(1-phenyl-4-(phenylimino)azetidin-2-yl)benzoate

¹H NMR (300 MHz, CDCl₃): δ 8.00 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.3 Hz,2H), 7.44-7.20 (m, 6H), 7.08-6.93 (m, 4H), 5.23 (dd, J=6.2, 3.0 Hz, 1H),3.54 (dd, J=14.7, 6.2 Hz, 1H), 2.92 (dd, J=14.7, 3.0 Hz, 1H), 1.58 (s,9H); HRMS-ESI (m/z) calcd for C₂₆H₂₇N₂O₂ [(M+H)⁺] 399.2073, found399.2111.

(E)-2-(2-(4-(2-phenyl-4-(phenylimino)azetidin-1-yl)phenoxy)ethoxy)ethan-1-ol

¹H NMR (300 MHz, CDCl₃): δ 7.47-7.22 (m, 9H), 7.09-6.96 (m, 3H),6.89-6.65 (m, 3H), 5.15 (dd, J=6.1, 2.9 Hz, 1H), 4.37-4.19 (m, 2H),4.15-4.01 (m, 2H), 3.92-3.70 (m, 4H), 3.50 (dd, J=14.7, 6.1 Hz, 1H),2.93 (dd, J=14.7, 2.9 Hz, 1H); HRMS-ESI (m/z) calcd for C₂₅H₂₇N₂O₃[(M+H)⁺] 403.2022, found 403.2008.

(E)-tert-butyl2-(4-(2-(4-chlorophenyl)-4-(phenylimino)azetidin-1-yl)phenoxy)acetate

To a stirred solution of azetidinimine 1 (30 mg, 0.086 mmol, see belowfor structure), and potassium carbonate (13 mg, 0.095 mmol, 1.1 equiv.)in dimethylformamide (DMF) (500 μL) is added t-butyl bromoacetate (18.5mg, 14 μL, 0.095 mmol, 1.1 equiv.). The reaction mixture is stirred at60° C. overnight (thin layer chromatography (TLC) monitoring) thenpurified by automated flash column chromatography using a gradient ofAcOEt in heptane (AcOEt 0%→20% over 20 min). Orange wax. (31 mg, 78%).

¹H NMR (300 MHz, CDCl₃): δ 7.37-7.26 (m, 8H), 7.06 (m, 3H), 6.83-6.79(m, 2H), 5.12 (dd, J=6.2, 2.8 Hz, 1H), 4.44 (s, 2H), 3.50 (dd, J=14.5,6.2 Hz, 1H), 2.90 (dd, J=14.5, 2.8 Hz, 1H), 1.47 (s, 9H). HRMS-ESI (m/z)calcd for C₂₇H₂₈ClN₂O₃ [(M+H)⁺] 463.1788, found: 463.1793.

(E)-tert-butyl2-(4-(2-phenyl-4-(phenylimino)azetidin-1-yl)phenoxy)acetate

To a stirred solution of azetidinimine 2 (36 mg, 0.115 mmol), andpotassium carbonate (32 mg, 0.095 mmol, 2 equiv.) in DMF (400 μL) isadded t-butyl bromoacetate (34 mg, 25 μL, 0.095 mmol, 1.5 equiv.). Thereaction mixture is stirred at 100° C. overnight (TLC monitoring) thenpurified by automated flash column chromatography using a gradient ofAcOEt in heptane (AcOEt 0%→20% over 20 min). Orange wax. (30.7 mg, 62%).

¹H NMR (300 MHz, CDCl₃): δ ¹H NMR (300 MHz, CDCl₃): δ 7.43-7.26 (m,10H), 7.02 (d, J=8.4 Hz, 2H), 6.80 (d, J=8.4 Hz, 2H), 5.14 (dd, J=6.0,3.0 Hz, 1H), 4.44 (s, 2H), 3.50 (dd, J=15.0, 6.0 Hz, 1H), 2.93 (dd,J=6.0, 3.0 Hz, 1H), 1.47 (s, 9H). HRMS-ESI (m/z) calcd for C₂₇H₂₉N₂O₃[(M+H)⁺] 429.2178, found: 429.2182.

(E)-4-(1-phenyl-4-(phenylimino)azetidin-2-yl)benzoic acid 4

This compound was obtained using general procedure C as a white foam in96%.

¹H NMR (300 MHz, MeOD): δ 8.03 (d, J=8.2 Hz, 2H), 7.52 (d, J=8.2 Hz,2H), 7.38 (d, J=8.2 Hz, 2H), 7.31-7.21 (m, 4H), 7.06-6.94 (m, 4H), 5.36(dd, J=6.0, 3.0 Hz, 1H), 3.59 (dd, J=15.0, 6.0 Hz, 1H), 2.89 (dd,J=15.0, 3.0 Hz, 1H). One proton missing due to chemical exchange withCD₃OD. HRMS-ESI (m/z) calcd for C₂₂H₁₉N₂O₂ [(M+H)⁺] 343.1447, found343.1430.

(E)-2-(4-(2-(4-chlorophenyl)-4-(phenylimino)azetidin-1-yl)phenoxy)aceticacid

This compound was obtained using general procedure C as a white foam in69%.

¹H NMR (300 MHz, MeOD): δ 7.44-7.27 (m, 8H), 7.08-7.05 (m, 3H), 6.87 (d,J=9.3 Hz, 2H), 5.31 (dd, J=5.7, 2.9 Hz, 1H), 4.46 (s, 2H), 3.58 (dd,J=14.7, 5.7 Hz, 1H), 2.95 (dd, J=14.7, 2.9 Hz, 1H). HRMS-ESI (m/z) calcdfor C₂₃H₁₉ClN₂O₃ [(M+H)⁺] 407.1162, found 407.1159.

(E)-2-(4-(2-phenyl-4-(phenylimino)azetidin-1-yl)phenoxy)acetic acid

This compound was obtained using general procedure C as a white foam in65%.

¹H NMR (300 MHz, MeOD): δ 7.43-7.25 (m, 10H), 7.04-6.99 (m, 3H), 6.84(d, J=9.4 Hz, 2H), 5.23 (dd, J=6.0, 2.8 Hz, 1H), 4.34 (s, 2H), 3.53 (dd,J=14.6, 6.0 Hz, 1H), 2.85 (dd, J=14.6, 2.8 Hz, 1H). HRMS-ESI (m/z) calcdfor C₂₃H₂₁N₂O₃ [(M+H)⁺] 373.1552, found 373.1545.

(E)-4-(2-phenyl-4-(phenylimino)azetidin-1-yl)phenol 2

This compound was obtained using general procedure D as a yellow oil in38%.

¹H NMR (300 MHz, CDCl₃): δ 7.41-7.23 (m, 10H), 7.07-7.03 (m, 3H), 6.68(d, J=8.9 Hz, 2H), 5.16 (dd, J=6.0, 2.9 Hz, 1H), 3.50 (dd, J=14.7, 6.0Hz, 1H), 2.92 (dd, J=14.7, 2.9 Hz, 1H), OH signal missing. HRMS-ESI(m/z) calcd for C₂₁H₁₉N₂O [(M+H)⁺] 315.1497, found 315.1503.

(E)-4-(2-(4-chlorophenyl)-4-(phenylimino)azetidin-1-yl)phenol 1

This compound was obtained using general procedure D as a yellow foam in60%.

¹H NMR (300 MHz, CDCl₃): δ 7.34-7.26 (m, 8H), 7.07-7.00 (m, 3H), 6.71(d, J=9.0 Hz, 1H), 5.13 (dd, J=6.0, 3.0 Hz, 1H), 3.50 (dd, J=14.8, 6.2Hz, 1H), 2.90 (dd, J=14.8, 3.0 Hz, 1H), OH signal missing. HRMS-ESI(m/z) calcd for C₂₁H₁₈ClN₂O [(M+H)⁺] 349.1108, found 349.1092.

(E)-4-(1-(4-methoxyphenyl)-4-(phenylimino)azetidin-2-yl)benzoic acid 3

This compound was obtained using general procedure D as a yellow foam in29%.

¹H NMR (300 MHz, CDCl₃): δ 8.04 (d, J=8.0 Hz, 2H), 7.47 (d, J=8.0 Hz,2H), 7.31-7.23 (m, 5H), 7.07-7.02 (m, 3H), 6.72 (d, J=8.0 Hz, 2H), 5.22(dd, J=15.0, 3.0 Hz, 1H), 3.91 (s, 3H), 3.54 (dd, J=15.0, 6.0 Hz, 1H),2.92 (dd, J=15.0, 3.0 Hz, 1H), carboxylic proton missing. HRMS-ESI (m/z)calcd for C₂₃H₂₁N₂O₃ [(M+H)⁺] 373.1552, found: 373.1546.

(E)-2-((tert-butoxycarbonyl)amino)ethyl4-(1-phenyl-4-(phenylimino)azetidin-2-yl)benzoate 5

To an argon-flushed and stirred solution of compound 4 in DCM (0.5 mL)is added triethylamine (1.2 mg, 2 μL, 0.07 mmol, 1 equiv.), CDI (11.7mg, 0.07 mmol, 1 equiv.) and tert-butyl (2-hydroxyethyl)carbamate (11.7mg, 0.07 mmol, 1 equiv.). The reaction mixture is stirred 16 h at rtthen purified by automated flash column chromatography using a gradientof AcOEt in heptane (AcOEt 0%→50% over 30 min) to afford a white foam.(14 mg, 38%).

¹H NMR (300 MHz, CDCl₃): δ 8.06 (d, J=9.0 Hz, 2H), 7.51 (d, J=9.0 Hz,2H), 7.41 (d, J=9.0 Hz, 2H), 7.33-7.23 (m, 4H), 7.08-6.96 (m, 4H), 5.25(dd, J=6.0, 3.0 Hz, 1H), 4.82 (m, 1H), 4.38 (t, J=5.0, 2H), 3.60-3.52(m, 3H), 2.93 (dd, J=15.4, 3.0 Hz, 1H), 1.43 (s, 9H). HRMS-ESI (m/z)calcd for C₂₉H₃₂N₃O₄ [(M+H)⁺] 486.2393, found 486.2375.

(E)-2-((4-(1-phenyl-4-(phenylimino)azetidin-2-yl)benzoyl)oxy)ethanaminium2,2,2-trifluoroacetate

To a solution of azetidinimine 5 (19 mg, 0.038 mmol) in DCM (100 μL) isadded TFA (trifluoroacetic acid, 100 μL, excess). The reaction mixtureis stirred at room temperature for 16 h then at 40° C. for 24 h.Subsequent evaporation of solvents furnished the title compound in theform of a TFA salt (19 mg, quant.).

¹H NMR (300 MHz, MeOD): δ 8.03 (d, J=8.3 Hz, 2H), 7.55-7.47 (m, 4H),7.42-7.40 (m, 1H), 7.34-7.30 (m, 2H), 7.03-6.97 (m, 2H), 6.58-6.53 (m,3H), 4.94 (dd, J=8.0, 6.0 Hz, 1H), 4.54-4.50 (m, 2H), 3.35 (t, J=5.7 Hz,2H), 2.90 (dd, J=15.2, 8.0 Hz, 1H), 2.79 (dd, J=15.2, 6 Hz, 1H). Threeprotons missing due to chemical exchange with MeOD. ¹⁹F NMR (282 MHz,MeOD): δ −76.87 (s, 3F). HRMS-ESI (m/z) calcd for C₂₄H₂₄N₃O₂ [(M+H)⁺]386.1869, found: 386.1862.

(E)-(4-(1-phenyl-4-(phenylimino)azetidin-2-yl)phenyl)methanol 6

A solution of azetidinimine 4 (40 mg, 0.2 mmol) under argon in anhydrousTHF (terahydrofuran, 0.6 mL) is cooled to 0° C. then LiAlH₄ (23 mg, 0.6mmol, 3 equiv.) is added. The reaction mixture is stirred 3 h at roomtemperature (TLC monitoring) then AcOEt and a saturated aqueous solutionof Na₂SO₄ are carefully added to quench the reaction. The resultingslurry is filtrated through a pad of celite and washed with additionalAcOEt. The organic layer is dried over sodium sulfate, filtered thenevaporated. Automated flash column chromatography using a gradient ofAcOEt in heptane (AcOEt 0%→30% over 20 min) furnished the title compoundas a white foam (51.2 mg, 79%).

¹H NMR (300 MHz, CDCl₃): δ 7.48-7.38 (m, 6H), 7.34-7.23 (m, 4H),7.09-6.95 (m, 4H), 5.20 (dd, J=6.0, 3.0 Hz, 1H), 4.70 (s, 2H), 3.52 (dd,J=14.7, 6.0 Hz, 1H), 2.93 (dd, J=14.7, 3.0 Hz, 1H), OH proton missing.HRMS-ESI (m/z) calcd for C₂₂H₂₁N₂O [(M+)⁺] 329.1654, found: 329.1643.

(E)-N-(4-(4-(chloromethyl)phenyl)-1-phenylazetidin-2-ylidene)aniline

A solution of azetidimine 6 (22 mg, 0.068 mmol) and triethylamine (14mg, 19 μL, 0.135 mmol, 2 equiv.) in DCM and under argon is cooled to 0°C. then MsCl (mesyl chloride, 8.5 mg, 6 μL, 0.074 mmol, 1.1 equiv.) isadded. The reaction mixture is stirred at rt overnight. Afterwards,additional DCM (10 mL) is added then the reaction mixture is washedtwice with water, dried over sodium sulfate and evaporated. Automatedflash column chromatography using a gradient of AcOEt in heptane (AcOEt0%→20% over 25 min) furnished the title compound as a colorless oil(19.2 mg, 70%).

¹H NMR (300 MHz, CDCl₃): δ 7.45-7.39 (m, 6H), 7.32-7.23 (m, 4H),7.08-6.95 (m, 4H), 5.19 (dd, J=6.0, 3.0 Hz, 1H), 4.59 (s, 2H), 3.51 (dd,J=14.6, 6.0 Hz, 1H), 2.92 (dd, J=14.6, 3.0 Hz, 1H). HRMS-ESI (m/z) calcdfor C₂₂H₂₀ClN₂ [(M+H)⁺] 347.1315, found: 347.1310.

(E)-N-(4-(4-(azidomethyl)phenyl)-1-phenylazetidin-2-ylidene)aniline

Step 1: A solution of 6 (148 mg, 0.45 mmol) and triethylamine (50 mg, 70μL, 0.5 mmol, 2 equiv.) in DCM and under argon is cooled to 0° C. thenMsCl (mesyl chloride, 57 mg, 39 μL, 0.5 mmol, 1.1 equiv.) is added. Thereaction mixture is stirred at rt overnight. Afterwards, additional DCM(10 mL) is added and the reaction mixture is washed twice with water.The aqueous layer is extracted with DCM then the organic layer is driedover sodium sulfate and evaporated to afford the crude benzylic chlorideintermediate. Step 2: To the previous crude residue is added DMF (0.5mL), NaN₃ (33 mg, 0.5 mmol, 1.1 equiv.) and KI (8 mg, 0.045 mmol, 10 mol%). The reaction mixture is stirred overnight at 50° C. under air.Automated flash column chromatography using a gradient of AcOEt inheptane (AcOEt 0%→20% over 25 min) furnished the title compound as acolorless oil (98 mg, 62%).

¹H NMR (300 MHz, CDCl₃): δ 7.49-7.47 (m, 4H), 7.37-7.26 (m, 6H),7.10-6.98 (m, 4H), 5.21 (dd, J=6.0, 3.0 Hz, 1H), 4.37 (s, 2H), 3.53 (dd,J=15.0, 6.0 Hz, 1H), 2.95 (dd, J=15.0, 3.0, 1H). HRMS-ESI (m/z) calcdfor C₂₂H₂₀N₅ [(M+H)⁺] 354.1719, found: 354.1727.

(E)-N-(1-phenyl-4-(4-((prop-2-yn-1-yloxy)methyl)phenyl)azetidin-2-ylidene)aniline

To a stirred solution of 6 (100 mg, 0.3 mmol) in anhydrous DMF and underargon is added NaH (13 mg, 0.33 mmol, 1.1 equiv.). After 10 min, a 70%wt. propargyl chloride solution in toluene (35 mg, 37 μL, 0.33 mmol, 1.1equiv.) is added. The reaction mixture is stirred overnight. Automatedflash column chromatography using a gradient of AcOEt in heptane (AcOEt0%→20% over 25 min) furnished the title compound as a colorless oil (26mg, 24%).

¹H NMR (300 MHz, CDCl₃): δ 7.46-7.37 (m, 6H), 7.33-7.22 (m, 4H),7.08-6.95 (m, 4H), 5.19 (dd, J=6.0, 3.0 Hz, 1H), 4.61 (s, 2H), 4.20 (d,J=2.0 Hz, 2H), 3.51 (dd, J=15.0, 6.0 Hz, 1H), 2.92 (dd, J=15.0, 3.0 Hz,1H), 2.48 (t, J=2.0, 1H). HRMS-ESI (m/z) calcd for C₂₅H₂₃N₂O [(M+H)⁺]367.1810, found: 367.1799.

1. Compound of formula (I):

characterized in that: R₁ represents a chemical moiety chosen in thegroup consisting of hydrogen, cyano, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl,C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkoxy, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl,(C₁-C₆)-haloalkoxy-(C₁-C₆)-alkyl, C₁-C₁₀ thioalkyl,(C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₁₀ alkylsulfinyl, C₁-C₁₀haloalkylsulfinyl, C₁-C₁₀ haloalkylsulfonyl, C₃-C₁₀ trialkylsilyl,C₁-C₁₀ alkylsulfonyl, C₅-C₁₂ arylsulfonyl, formyl, C₂-C₁₀ alkylcarbonyl,C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy,C₂-C₁₀ alkenylthio, C₂-C₁₀ alkynylthio, C₁-C₁₀ haloalkyl, C₂-C₁₀haloalkenyl, C₂-C₁₀ haloalkynyl, C₂-C₁₀ haloalkylcarbonyl, C₁-C₁₀haloalkylthio, C₂-C₁₀ haloalkenyloxy, C₂-C₁₀ haloalkynyloxy, C₂-C₁₀haloalkenylthio, C₂-C₁₀ haloalkynylthio, (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl,(C₅-C₁₂)-aryl-(C₁-C₆)-alkyl ester or a mono or polycyclic C₅-C₁₂ aryl ormono or polycyclic C₃-C₁₂ heteroaryl fragments, wherein the aryl orheteroaryl fragments are optionally substituted by one or severalhalogen atoms, hydroxyl (OH), nitro, cyano, formyl, C₁-C₆ alkyl, C₃-C₇cycloalkyl, amino-C₁-C₁₀ alkoxy, (carboxylic acid)-C₁-C₁₀ alkoxy,(carboxylic (C₁-C₆)alkyl ester)-C₁-C₁₀ alkoxy, (1,2 diol)-C₂-C₁₀ alkoxy,—O—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-OH, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, C₂-C₆alkylcarbonyl, C₁-C₆ alkylthio, C₁-C₆ thioalkyl,(C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkoxyalkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio, C₁-C₆haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆ trialkylsilyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₂-C₆ haloalkenyl, C₂-C₆haloalkenyloxy, C₂-C₆ haloalkynyloxy, C₂-C₆ alkenyloxy, C₂-C₆alkynyloxy, C₂-C₆ alkenylthio, C₂-C₆ alkynylthio, C₂-C₆ haloalkenylthio,C₂-C₆ haloalkynylthio and/or a C₁-C₆ alkoxy optionally substituted by amono or polycyclic C₅-C₁₂ aryl group, and/or a bridging group of formula—O—CH₂—O— or —O—CH₂CH₂—O—; R₂, R₃, R₄ and R₅, independently one fromeach other, represent a chemical moiety chosen in the group consistingof hydrogen, halogen, nitro, cyano, C₁-C₁₀ alkyl, C₃-C₁₀ cycloalkyl,C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkoxy, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl,(C₁-C₆)-haloalkoxy-(C₁-C₆)-alkyl, C₁-C₁₀ thioalkyl,(C₅-C₁₂)-aryl-(C₁-C₆)-alkyl ester, (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl,C₁-C₁₀ alkylsulfinyl, C₁-C₁₀ haloalkylsulfinyl, C₁-C₁₀haloalkylsulfonyl, C₃-C₁₀ trialkylsilyl, C₁-C₁₀ alkylsulfonyl, C₅-C₁₂arylsulfonyl, formyl, C₂-C₁₀ alkylcarbonyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₂-C₁₀ alkenyloxy, C₂-C₁₀ alkynyloxy, C₂-C₁₀ alkenylthio,C₂-C₁₀ alkynylthio, C₁-C₁₀ haloalkyl, C₂-C₁₀ haloalkenyl, C₂-C₁₀haloalkynyl, C₂-C₁₀ haloalkylcarbonyl, C₁-C₁₀ haloalkylthio, C₂-C₁₀haloalkenyloxy, C₂-C₁₀ haloalkynyloxy, C₂-C₁₀ haloalkenylthio, C₂-C₁₀haloalkynylthio, (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl or a mono or polycyclicC₅-C₁₂ aryl or mono or polycyclic C₃-C₁₂ heteroaryl fragments, whereinthe aryl or heteroaryl fragments are optionally substituted by one orseveral halogen atoms, nitro, cyano, formyl, COOH, —COO(C₁-C₆ alkyl),C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ N₃-substituted alkyl, C₁-C₆NH₂-substituted alkyl, C₁-C₆ alcohol, C₁-C₆ alkoxy,(C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, C₂-C₆ alkylcarbonyl, C₁-C₆ alkylthio,C₁-C₆ thioalkyl, (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₆ alkylsulfinyl,C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkoxyalkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio, C₁-C₆haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆ trialkylsilyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₂-C₆ haloalkenyl, C₂-C₆haloalkenyloxy, C₂-C₆ haloalkynyloxy, C₂-C₆ alkenyloxy, C₂-C₆alkynyloxy, C₂-C₆ alkenylthio, C₂-C₆ alkynylthio, C₂-C₆ haloalkenylthio,C₂-C₆ haloalkynylthio, a monocyclic C₅-C₆ aryl group optionallysubstituted by a C₁-C₆ alkyloxy group and/or a COO(C₁-C₆ alkyl) groupwherein the alkyl is substituted by NH₂ or NHCOO(C₁-C₆)alkyl orNHCOO(C₁-C₆)alkyl(mono or polycyclic C₅-C₁₂)aryl; R₆ represents a monoor polycyclic C₅-C₁₂ aryl fragment, wherein the aryl fragment isoptionally substituted by one or several halogen atoms, cyano, formyl,nitro, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ alkoxy,(C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, C₂-C₆ alkylcarbonyl, C₁-C₆ alkylthio,C₁-C₆ thioalkyl, (C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₆alkylsulfinyl,C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkoxyalkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio, C₁-C₆haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆ trialkylsilyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₂-C₆ haloalkenyl, C₂-C₆haloalkenyloxy, C₂-C₆ haloalkynyloxy, C₂-C₆ alkenyloxy, C₂-C₆alkynyloxy, C₂-C₆ alkenylthio, C₂-C₆ alkynylthio, C₂-C₆ haloalkenylthio,C₂-C₆ haloalkynylthio fragments, and/or a monocyclic C₅-C₆ aryl groupoptionally substituted by a C₁-C₆ alkyloxy group; provided that at leasttwo of R₃, R₄ and R₅ represent a hydrogen atom and R₆ is not asubstituted or unsubstituted —SO₂-phenyl group such as a tosyl group. 2.The compound according to claim 1 characterized in that R₆ represents aR₆ represents a mono or polycyclic C₅-C₁₂ aryl fragment, optionallysubstituted by one or several halogen atoms, C₁-C₆ haloalkyl or C₁-C₆alkoxy.
 3. Compound according to claim 1 or 2, characterized in that R₁represents a monocyclic aryl fragment optionally substituted by one orseveral (notably 1 to 3) OH, C₁-C₆ alkyl, C₁-C₆ thioalkyl, halogen,amino-(C₁-C₁₀ alkoxy), (carboxylic acid)-(C₁-C₁₀ alkoxy), (carboxylic(C₁-C₆)alkyl ester)-C₁-C₁₀ alkoxy, (1,2 diol)-C₂-C₁₀ alkoxy,—O—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-OH, (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl ester,nitro and/or a C₁-C₆ alkoxy group optionally substituted by a mono orpolycyclic C₅-C₁₂ aryl group, and/or a bridging group of formula—O—CH₂—O— or —O—CH₂CH₂—O—, preferably R₁ represents a monocyclic arylfragment optionally substituted by one or several C₁-C₆ alkoxy, C₁-C₆thioalkyl, halogen, amino-(C₁-C₁₀ alkoxy), (carboxylic acid)-(C₁-C₁₀alkoxy), (1,2 diol)-(C₂-C₁₀ alkoxy), (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl esterand/or nitro fragments.
 4. Compound according to any one of claims 1 to3, characterized in that R₂ and/or R₃ represent a monocyclic aryl,monocyclic heteroaryl or polycyclic aryl fragment optionally substitutedby one or several (notably 1 to 3) halogen atoms, COOH, —COO(C₁-C₆alkyl), C₁-C₆ N₃-substituted alkyl, C₁-C₆ haloalkyl, C₁-C₆ alcohol,C₁-C₆ alkoxy, C₁-C₆ thioalkyl, C₁-C₆ acyl, nitro, cyano and/or aCOO(C₁-C₆ alkyl) group wherein the alkyl is substituted by NH₂ orNHCOO(C₁-C₆)alkyl or NHCOO(C₁-C₆)alkyl(mono or polycyclic C₅-C₁₂)aryl,fragments.
 5. Compound according to any one of claims 1 to 4,characterized in that R₃, R₄ and R₅ represent hydrogen atoms. 6.Compound according to any one of claims 1 to 5, characterized in that itis

a solvate or a salt thereof.
 7. Method to prepare a compound accordingto any one of claims 1 to 6 including the explicitly excluded compoundsof claim 1 characterized in the following steps: a. to a compound offormula (II):

wherein R₄ and R₆ are as defined in any one of claims 1 to 6 includingthe excluded definitions of claim 1, and R₇ represents a leaving groupsuch as amides, sulfonyles, or oxy-carbonyls, optionally, R₆—N—R₇ mayform at least one ring wherein R₆ and R₇ directly linked one to eachother and wherein said ring comprises from 3 to 12 atoms chosen from C,N, O, S, B and P, substituted by at least one hydrogen, oxygen,nitrogen, hydroxyl, thiol, amine, cyano, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl,(C₁-C₆)-haloalkoxy-(C₁-C₆)-alkyl, C₁-C₆ thioalkyl,(C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆ trialkylsilyl, C₁-C₆alkylsulfonyl, C₅-C₁₂ arylsulfonyl, formyl, C₂-C₆ alkylcarbonyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₂-C₆ alkenyloxy, C₂-C₆ alkynyloxy, C₂-C₆alkenylthio, C₂-C₆ alkynylthio, C₁-C₆ haloalkyl, C₂-C₆ haloalkenyl,C₂-C₆ haloalkynyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio, C₂-C₆haloalkenyloxy, C₂-C₆ haloalkynyloxy, C₂-C₆ haloalkenylthio, C₂-C₆haloalkynylthio, (C₅-C₁₂)-aryl-(C₁-C₆)-alkyl or a mono or polycyclicC₅-C₁₂ aryl or mono or polycyclic C₃-C₁₂ heteroaryl fragments, whereinthe aryl or heteroaryl fragments are optionally substituted by one orseveral halogen atoms, nitro, cyano, formyl, C₁-C₆ alkyl, C₃-C₇cycloalkyl, C₁-C₆ alkoxy, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, C₂-C₆alkylcarbonyl, C₁-C₆ alkylthio, C₁-C₆ thioalkyl,(C₁-C₆)-alkylthio-(C₁-C₆)-alkyl, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkoxyalkyl, C₂-C₆ haloalkylcarbonyl, C₁-C₆ haloalkylthio, C₁-C₆haloalkylsulfinyl, C₁-C₆ haloalkylsulfonyl, C₃-C₆ trialkylsilyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₂-C₆ haloalkynyl, C₂-C₆ haloalkenyl, C₂-C₆haloalkenyloxy, C₂-C₆ haloalkynyloxy, C₂-C₆ alkenyloxy, C₂-C₆alkynyloxy, C₂-C₆ alkenylthio, C₂-C₆ alkynylthio, C₂-C₆ haloalkenylthio,C₂-C₆ haloalkynylthio and/or nitro fragments; is added a compound offormula (III):

wherein R₁, R₂ and R₃ are as defined in any one of claims 1 to 5 in thepresence of a base B1, preferably R₁ is an electro-donating group and/orR₂ and/or R₃ are electron-withdrawing groups, preferably undermicrowaves, advantageously step (a) is carried out under pressure and/orat a temperature above 50° C., and in particular without the presence ofa metal compound, such as copper, whether it is in its metallic or oneof its oxidized or reduced forms; b. an optional addition step of R₅ asdefined in any one of claims 1 to 5 through a nucleophilic addition tothe compound obtained in step a., preferably with R5-X, wherein X is ahalogen atom in the presence of a base B2; c. retrieving the compound offormula (I) as defined in any one of claims 1 to
 5. 8. Compound offormula (II) according to claim 7, or its equivalent carbine, preferablyas synthesis intermediate.
 9. Compound of formula (I) as defined in anyone of claims 1 to 6 or as defined in claim 7 for use as an inhibitor ofa carbapenemase enzyme, preferably of a NDM-1 type, OXA-48 type or aKPC-type enzymes.
 10. Compound of formula (I) as defined in any one ofclaims 1 to 6 or as defined in claim 7 for its use in combination withan antibiotic.
 11. Pharmaceutical composition comprising at least onecompound of formula (I) as defined in any one of claims 1 to 6 or asdefined in claim 7, and a pharmaceutically acceptable carrier.
 12. Thepharmaceutical composition of claim 11, characterized in that itcomprises a second active substance, such as an antibiotic.
 13. Compoundof formula (I) as defined in any one of claims 1 to 6 or as defined inclaim 7, or composition according to claim 11 or 12, for use as a drug.14. The compound or composition for use of claim 13, characterized inthat the drug is an antibiotic.
 15. The compound or composition for useaccording to claim 10 or 14 characterized in that the antibiotic iseffective on bacteria chosen from gram-negative bacteria such asEnterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii,preferably drug resistant forms of gram-negative bacteria to one orseveral classes of antibiotics comprising β-lactams by production of aβ-lactamase.
 16. A kit comprising: at least one first containercontaining a first therapeutically active compound of formula (I) asdefined in any one of claims 1 to 6 or as defined in claim 7 andmixtures thereof, and at least one second container containing a secondtherapeutically active substance which is an antibiotic, as acombination product for simultaneous, sequential and separate use, inparticular in antibiotherapy.